The objective of this study was to investigate alterations to brain activity and functional connectivity in patients with tinnitus, exploring neural features in the transition from acute to chronic phantom perception. Twenty‐four patients with acute tinnitus, 23 patients with chronic tinnitus, and 32 healthy controls were recruited. High‐density electroencephalography (EEG) was used to explore changes in brain areas and functional connectivity in different groups. When compared with healthy subjects, acute tinnitus patients had a significant reduction in superior frontal cortex activity across all frequency bands, whereas chronic tinnitus patients had a significant reduction in the superior frontal cortex at beta 3 and gamma frequency bands as well as a significant increase in the inferior frontal cortex at delta‐band and superior temporal cortex at alpha 1 frequency band. When compared to the chronic tinnitus group, the acute tinnitus group activity was significantly increased in the middle frontal and parietal gyrus at the gamma‐band. Functional connectivity analysis showed that the chronic tinnitus group had increased connections between the parahippocampus gyrus, posterior cingulate cortex, and precuneus when compared with the healthy group. Alterations of local brain activity and connections between the parahippocampus gyrus and other nonauditory areas appeared in the transition from acute to chronic tinnitus. This indicates that the appearance and development of tinnitus is a dynamic process involving aberrant local neural activity and abnormal connectivity in multifunctional brain networks. Our findings suggested that the appearance and development of tinnitus is a dynamic process involving aberrant local neural activity and abnormal connectivity in multifunctional brain networks. The alterations of local brain activity and connections between the parahippocampus gyrus and other nonauditory areas appeared in the transition from acute to chronic tinnitus, which appear important to identify the neural predictors for the development of tinnitus and prevention of transition from acute to chronic tinnitus. As a common clinical symptom tinnitus is experienced constantly by 10–15% of the adult population  and 23 patients with chronic tinnitus (duration more than 6 months) were recruited from the Ear, Nose and Throat clinic, Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University.Patients had sought clinical help for their tinnitus.Patients with conductive or mixed hearing loss were excludedPatients had no history of use of ototoxic drugsSubjects with middle ear surgery, pulsatile tinnitus, Ménière's disease, autoimmune hearing loss, acoustic neurinoma, central nervous system disorders, and head trauma were excluded.The selection criteria for subjects with tinnitus were:Thirty‐two healthy controls without tinnitus were also recruited. None of participants was reported comorbid conditions alongside tinnitus such as hypertension, hyperacusis, depression, epilepsy. Acute tinnitus patient data were collected prior to receiving any therapeutic intervention. All participants were provided with information about this study and signed a written consent form. This research was approved by the Institution Review Board of The Sun Yat‐sen Memorial Hospital.2.2All participants were interviewed to obtain a thorough case history including; age, duration of tinnitus, side of tinnitus and any other pathologies. This was followed by otoscopic examination, pure tone audiometry and a tinnitus matching test. The hearing threshold was determined using pure tone audiometry: air conduction hearing thresholds were measured at frequencies between 125 and 8,000 Hz with an octave interval. In addition, bone conduction hearing thresholds were measured at 250, 500, 1,000, 2000, and 4,000 Hz. Mean hearing threshold was calculated as the average of hearing thresholds at 500, 1000, 2000, and 4,000 Hz  were used to approximately match the tinnitus pitch. Subjects were asked to compare their perceived tinnitus pitch with different matching tones until the tone exactly matching their tinnitus was obtained. If no pure tone was obtained, narrowband noise was used. After confirming tinnitus pitch, the level was set 5 dB above the measured audiometric threshold to give an approximate tinnitus loudness level, which was then adjusted in 1 dB step until the subject reported that the tone matched the loudness of their tinnitus  was used to evaluate tinnitus severity and level of tinnitus handicap, according to 0–100 increasing handicap scale. Participants completed the THI prior to the experiment.2.5A high‐density EEG with 128channels  and a NetAmps 200 amplifier was applied to collect resting‐state EEG data from all participants. Subjects were instructed to sit in a comfortable chair and remain calm. Subjects were then required to keep their eyes open and fixate a cross mark in front of them. The EEG recording lasted ~7 min. The CZ electrode was used as reference. The sampling rate was 1,000 Hz. Impedances were kept to less than 50 kΩ.2.6EEGLAB for v13.0.0 toolbox in MATLAB for R2013a was used to preprocess the raw EEG data. Firstly, the data were re‐referenced against the mean reference for all electrodes. The sampling rate was adjusted to 0.5 kHz. A notch filter was implemented at 50 Hz and the signals were band‐pass‐filtered from 0.5 to 100 Hz. Gross artifacts were manually removed by visual inspection. Artifacts originating from one or a few distinct sources or a limited volume of space were removed. In addition, other artifacts characterized by a particular temporal pattern such as exponential decay were removed using an independent component analysis (ICA) algorithm.The advantages of the ICA algorithm can be viewed in the literature   was used to explore the activity of brain areas in three groups and find any abnormal activity of brain areas in acute and chronic tinnitus patients. After mean reference transformation was applied, the sLORETA algorithm was used to calculate neuronal activity as current density  and nonlinear dependence  between the multivariate time series were measured  connectivity was calculated. After filtering the EEG data, the instantaneous phase was calculated using the Hilbert transform. More precisely, the data was decomposed into a limited number of cosine and sine waves at the Fourier frequencies using the discrete Fourier transform. sLORETA was applied to extract current density for regions of interest (ROI) over time. Power in all voxels was normalized to a power of 1 and log transformed at each time point. As a result, ROI values reflect the log transformed fraction of total power across all voxels for specific frequencies. ROI was confirmed based on a previous study, as shown in Table 2.8t statistic for independent groups with a threshold of p < .01 (corrected for multiple comparison). A correction for multiple comparisons in SnPM using random permutation has been shown to yield similar results with those acquired from a statistical parametric mapping approach using a general linear model with multiple comparisons corrections. For lagged connectivity differences, we compared differences between the chronic tinnitus and healthy control groups, between the chronic tinnitus and acute tinnitus groups and between the acute tinnitus and healthy control groups for each contrast using the t statistic for independent groups with a corrected threshold of p < .05. The significance threshold was based on a permutation test with 5,000 permutations.A non‐parametric statistical analysis of LORETA‐KEY images  was used to compare differences in resting‐state EEG activity between the patient groups using LORETA‐KEY's built‐in voxel‐wise randomization tests  and a 3p > .05). In addition, no significant difference was found between patient groups in terms of age  and gender .The characteristics of acute and chronic tinnitus patients were summarized in Table p < .05). In contrast, compared with the healthy subjects, chronic tinnitus patients had reduced brain activity in the superior frontal cortex (BA 6) for beta 3 and gamma frequency bands. In addition, chronic tinnitus subjects had a significant increase brain activity in the inferior frontal cortex (BA 47) for the delta‐band and the superior temporal cortex (BA 13) for alpha 1 frequency band when compared with the healthy subjects . The acute tinnitus group activity was however significantly increased in the middle frontal gyrus and the parietal gyrus  for gamma‐band when compared to the chronic tinnitus group . No significant difference was found in other brain areas and frequencies.Acute tinnitus patients had a significant reduction in superior frontal cortex (BA 6) activity across all frequency bands when compared with the healthy subjects . However, no significant connectivity change was found in acute tinnitus patients when compared with healthy subjects or chronic tinnitus patients.When compared with the healthy group, significantly increased functional connections were shown in chronic tinnitus patients between the parahippocampus gyrus BA 21) and the posterior cingulate cortex (PCC) (BA 18) as well as between the parahippocampus gyrus (BA 22) and precuneus (BA 28) under the lagged phase synchronization analysis  could be detected in patients with either acute or chronic tinnitus. The SFC has been regarded as the integrative hub of tinnitus that organizes efferent impulses to ensure coordination of the central nervous system  and the parietal gyrus of the acute tinnitus group when compared to the chronic tinnitus patients. The parietal gyrus is traditionally considered to be involved with attention, perceptual decision making and sensorimotor transformations  activity in the inferior frontal cortex (IFC) and superior temporal cortex (STC). IFG acts as an executive control component in the attention system that regulates dorsal and ventral attention networks  were found only when the chronic tinnitus group was compared to the control group. Based on a hypothesis .5With increase in tinnitus duration neural activity in the frontal, parietal and temporal cortices changed continuously and connectivity between the parahippocampus gyrus and other nonauditory areas appeared gradually. This study indicates that the occurrence and development of tinnitus is a dynamic process from abnormal local neural activity to abnormal connectivity in multifunctional brain networks. Particularly, the present results suggest that alterations of local brain activity and connections between the parahippocampus gyrus and other nonauditory areas may predict the transition from acute to chronic tinnitus and the parahippocampus gyrus appears a key hub in the central mechanism of tinnitus.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Back pain and mental health are related. The relationship may differ by socioeconomic status (SES); yet, research has not examined the moderating role of perceived SES. We examined if the association between back pain and poor mental health is more pronounced for older men with lower perceived SES. We used a sample of community-dwelling older men (>65yrs) with back pain from the Osteoporotic Fractures in Men Study . Participants reported their perceived SES in comparison to others in the community and in the nation (1=lowest—10=highest), back pain severity (mild—severe), and frequency . Mental health was assessed with the 12-item Short Form Health Survey. Analyses were adjusted for sociodemographic and health covariates. Greater pain severity and higher pain frequency were associated with poorer mental health (p<.001). Only severe pain was associated with poorer mental health (p<.001). Pain ‘some of the time’ (p=.02), ‘most of the time’ (p=.02), and ‘all of the time’ (p=.001) were associated with poorer mental health. Adverse effects of pain were reduced with greater community SES  and greater national SES . Reports of pain were worse for individuals with lower SES. Adverse associations of severe and high frequency back pain with poor mental health are more apparent in older men with lower perceived SES. Where one ranks oneself within their community or nation can influence the pain and mental health link.


Light‐driven biocatalytic processes are notoriously hampered by poor penetration of light into the turbid reaction media. In this study, wirelessly powered light‐emitting diodes are found to represent an efficient and scalable approach for process intensification of the photobiosynthetic production of diesel alkanes from renewable fatty acids. Setting light to fatty acids: The photodecarboxylation of fatty acids to alkanes presents an intriguing way of producing biodiesel. Using delocalized wirelessly powered internal illumination leads to a reaction that is more efficient, dramatically accelerated, and readily scalable, clearly pointing towards industrial implementation. Even though the actually achieved energy efficiency in this non‐optimized lab setup was 32.1 %, already 89.8 % appear possible with the AQY reached here by optimizing the setup to match state‐of‐the‐art efficiencies for the electronic parts and the inductively coupled energy transferAt perfect quantum efficiency and assuming loss‐free photon generation, the maximum theoretical energy efficiency of the reaction [ΔCvFAP (TON=molproduct×molCvFAP−1) never exceeded 9.000. These turnover numbers are well in the range of TONs previously observed for CvFAP[CvFAP inactivation. This supports the CvFAP inactivation mechanism proposed by Scrutton and co‐workers, assuming that intermediate radical species occurring in the catalytic mechanism may cause inactivation of the biocatalyst.Using homogeneously dissolved fatty acids does not represent a scalable approach for the large‐scale transformation of fatty acids into alkanes due to the low product titers. We therefore also investigated a two liquid phase approach to increase the overall payload of the fatty acids in the reactor system. For this, we chose triolein as the organic phase (representing future oil phases) to form a 200 mM solution of palmitic acid. More than 50 % conversion was achieved within 2 h with a rate similar to the one achieved in the monophasic system. However, at this point the product formation abruptly ceased . Further addition of fresh catalyst resulted in further product formation. This experiment highlights the current limitation of the proposed photobiocatalytic alkane production system being the comparably poor long‐term stability of the enzyme catalyst under process conditions. In our experiments the turnover numbers for CvFAP. Already, (photon) saturation effects become apparent which probably make further intensification challenging. Nevertheless, at the productivity achieved in this study, the process could produce 264 mL of pentadecane per liter of reaction volume each day, clearly pointing towards larger scale implementation. This study, however, also revealed a current shortcoming of the proposed photosynthetic fuel generation being the rather low operational stability of CvFAP, which needs further improvement. The low turnover numbers mean that the enzyme needs to be continuously replenished, resulting in a high cost contribution of the biocatalyst.CvFAP  are still comparably low,E. coli cells in the reaction. Optimization of the expression conditions will alleviate this issue. On the other hand, we are convinced that further improvements can be expected from fermentation optimization and protein engineering resulting in more robust enzyme variants to render the envisioned photosynthetic production of alkanes economically feasible.In the present study, we have demonstrated that the rate of photobiocatalytic reactions, such as the decarboxylation of fatty acids, can be dramatically increased by using intensified internal illumination. The same technique also allows to seamlessly scale‐up the production volume to industrially relevant dimensions. The conditions presented herein seem to approach the limit for wild type The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


The rapid proliferation of intelligent systems  in today's society relies on sensors with low latency and computational effort. Yet current sensing systems ignore most available a priori knowledge, notably in the design of the hardware level, such that they fail to extract as much task‐relevant information per measurement as possible. Here, a “learned integrated sensing pipeline” (LISP), including in an end‐to‐end fashion both physical and processing layers, is shown to enable joint learning of optimal measurement strategies and a matching processing algorithm, making use of a priori knowledge on task, scene, and measurement constraints. Numerical results demonstrate accuracy improvements around 15% for object recognition tasks with limited numbers of measurements, using dynamic metasurface apertures capable of transceiving programmable microwave patterns. Moreover, it is concluded that the optimal learned microwave patterns are nonintuitive, underlining the importance of the LISP paradigm in current sensorization trends. Optimal wavefronts to probe a scene with microwave radiation in order to recognize objects therein are learned by integrating a model of the sensor's reconfigurable physical layer into the machine‐learning pipeline used to process the measurements. Thereby the amount of task‐relevant information obtained per measurement is maximized, enabling sensing with low latency and computational burden. The resulting measurements are then processed to answer a particular question. Usually, acquisition and processing are treated and optimized separately. For instance, the spatial resolution of a LIDAR system on an autonomous vehicle is often optimized to be as high as possible, while its resulting measurements are subsequently processed to detect pedestrians with as high an accuracy as possible. Recently, machine learning (ML) techniques have dramatically improved the accuracy of measurements postprocessing for complex tasks (like object recognition) without requiring explicit analytical instructions.However, to date, the physical acquisition layers of context‐aware systems have yet to reap the benefits of new ML techniques. At the same time, by separately optimizing acquisition hardware and postprocessing software, most sensing setups are not tailored to their specific sensing task. Instead, as with the LIDAR example noted above, hardware is typically optimized to obtain a high‐fidelity visual image for human consumption, thereby often ignoring available knowledge that could help to highlight information that is critical for ML‐based analysis.Here, we address both of the above shortcomings with a new “learned sensing” paradigm for context‐aware systems that allows for joint optimization of acquisition hardware and postprocessing software. The result is a device that acquires nonimaging data that is optimized for a particular ML task. We consider the challenge of identifying settings of a reconfigurable metamaterial‐based device emitting microwave patterns that can encode as much relevant information about a scene for subsequent ML‐based classification with as few measurements as possible. However, as we will detail, this framework is general, flexible, and can impact a number of future sensing scenarios.2The simplest approach in terms of the transceiver hardware is often to use random illuminations, for instance, by leveraging the natural mode diversity available in wave‐chaotic or multiply scattering systems.These “generic” illuminations fail to efficiently highlight salient features for task‐specific sensing, which is necessary to reduce the number of required measurements. In other words, they do not discriminate between relevant and irrelevant information for the task at hand. Task‐specific optimal illumination can be challenging to determine, due to hardware constraints , possible coupling effects between different transceivers, and in particular a lack of insight into the inner workings of the ML network  used to process the acquired data for each task.So far, most attempts at task‐specific tailored illuminations seek to synthesize illumination wavefronts matching the expected principal components of a scene.We hypothesize that wave‐based sensing can benefit from joint optimization of data acquisition and processing, making use of all available a priori knowledge. Inspired by recent works in the optical domain,3As noted above, we apply our concept to classification tasks with microwave sensors which are a crucial stepping stone toward numerous context‐aware systems. Microwave sensors can operate through optically opaque materials such as clothing, are not impacted by external visible lighting and scene color, minimally infringe upon privacy  and may eventually help sense through fog, smoke, and “around‐the‐corner.”We focus on optimally configuring dynamic metasurface hardware, a promising alternative to more traditional antenna arrays for beam‐forming and wavefront shaping.FigureN metamaterial elements are patterned into one of the waveguide surfaces to couple the energy to free space. An example of a metamaterial element that could be used is the tunable complimentary electric‐LC (cELC) elementf0 =  10 GHz depending on the bias voltage of two PIN diodes connected across its capacitive gaps. The N metamaterial elements are randomly distributed within a chosen aperture size (30 cm  ×  30 cm) but a minimum distance between elements of one free‐space wavelength is imposed.The reconfigurable metasurface aperture that we consider for the generation of shaped wavefronts is depicted in 4To demonstrate our proposed learned integrated sensing pipeline (LISP), we jointly optimize the illumination and detection properties of dynamic metasurface transceivers, along with a simple neural network classifier, for the task of scene classification. We consider the dummy task of recognizing “handwritten” metallic digits in simulation. Replacing this dummy task with a more realistic scenario, such as concealed‐threat detection, hand‐gesture recognition, or fall detection, is conceptually straightforward. To construct the LISP, we first formulate an analytical forward model of the measurement procedure. Second, we allow certain key parameters within the “physical” forward model to act as unknown weights  that we aim to optimize over. Third, we merge this weighted physical model into an ANN classifier, and use supervised learning to jointly train the unknown weights in both to maximize the system's classification accuracy.FigureWe establish an analytical forward model of our sensor's physical layer built upon a compact description of the metamaterial elements as dipoles. This dipole approximation is facilitated by the intrinsic sub‐wavelength nature of the metamaterial elements. As detailed in Section I in the Supporting Information, our forward model consists of three steps: i) extracting each metamaterial element's dipole moment while taking tuning state and interelement coupling into account;M distinct patterns. Each pattern corresponds to a specific pair of TX and RX metasurface configurations. Since our scheme is monochromatic, each measurement yields a single complex value ig. As shown in Figure M complex‐valued measurement vector is fed into a processing ANN. The latter consists of two fully connected layers, as shown in Figure A single measurement, depending on various factors such as the sensing task's complexity, the type of scene illumination but also the signal‐to‐noise ratio, may not carry enough information to successfully complete the desired sensing task.We can now assemble our pipeline consisting of an analog and two digital layers as outlined above Figure . The inptj,i in Figure The weights are trained by error backpropagation5M = 4 measurements and N = 64 metamaterial elements per metasurface. The dipole moments and scene illuminations corresponding to the four learned metasurface configurations are displayed in FigureWe begin by considering a single realization with FigureM and N. Since the ANN weights are initialized randomly before training, we conduct 40 realizations for each considered parameter combination. Averaging over realizations allows us to focus on the role of M and N without being sensitive to a given realization. Moreover, we can see the extent to which different realizations converge to similar results.In M gets larger, since the nonoverlapping illuminations can extract marginally more information about the scene. Yet the information that random and orthogonal illuminations encode in the measurements is not necessarily task‐relevant. The PCA‐based approach presents a noticeable performance improvement over generic illuminations because it makes use of a priori knowledge about the scene; yet it remains well below the attainable performance with our LISP because it ignores available a priori knowledge about the measurement constraints and the task. The PCA‐based approach is quite sensitive to the number of tunable elements in the dynamic metasurface (keeping the same aperture size), since beam synthesis works better with more degrees of freedom. In contrast, using only 16 instead of 64 metamaterial elements yields almost identical sensing performance with our LISP, highlighting our LISP's ability to successfully perform sensing tasks with a very light hardware layer.Random illuminations yield the worst performance out of the four considered paradigms. Orthogonal illuminations yield a marginal improvement over random illuminations as the number of measurements M ≤ 5, our scheme yields gains in accuracy of the order of 10–15% which is a substantial improvement in the context of classification tasks.M = 5 at 95%, meaning that we manage to extract all task‐relevant information to distinguish ten classes with only five measurements. The compression is enabled by the sparsity of task‐relevant features in the scene. Yet our scene is not sparse in the canonical basis: our region of interest corresponds to the size of the metallic digits. Unlike traditional computational imaging schemes that multiplex all scene information across measurements taken with a set of diverse  illumination patterns, the compression here comes from the discrimination between relevant and irrelevant information in a dense scene. Our LISP thus achieves a significant dimensionality reduction by optimally multiplexing task‐relevant information from different parts of the scene in the analog layer. The dimensionality reduction brings about a double advantage with respect to timing constraints: taking fewer measurements takes less time, and moreover less data has to be processed by the digital layers. In our (not heavily optimized) ANN architecture, the computational burden of the first digital ANN layer is directly proportional to the number of measurements M.For M ≥ 4, all other benchmark illumination schemes continue to fluctuate by several percent of classification accuracy. Our scheme's performance is thus reliable whereas any of the other benchmarks in any given realization may (taking the worst‐case scenario) yield a classification accuracy several percent below its average performance. Performance reliability of a sensor is important for deployment in real‐life decision‐making processes.A striking difference in the performance fluctuations, evidenced by the error bars in Figure 6M illuminations, we compute the mutual overlap between different illuminations. In the following, we define the overlap O of two scene illuminations A(ζ) and B(ζ) asM = 4 is shown in Figure The inferior performance of orthogonal and PCA‐based illuminations suggests that the task‐specific learned LISP illuminations do not trivially correspond neither to a set of optimally diverse illuminations nor to the principal components of the scene. To substantiate this observation, we analyze the scene illuminations in more detail. First, within a given series of N = 64 as opposed to N = 16, and of course the more illuminations we want to be mutually orthogonal the harder the task becomes. While radiating orthogonal wavefronts with the dynamic metasurface is not the best choice for sensing, it may well find applications in wireless communication.N. This is indeed the average overlap of two random complex vectors of length 10, 10 corresponding roughly to the number of independent speckle grains in the scene—see Figure In Figure M, saturates around 21.5% and 24.5% for N = 64 and N = 16, respectively, and is hence lower than that of random illuminations. In principle, if beam synthesis worked perfectly, the PCA‐based patterns should not overlap at all since PCA modes are orthogonal by definition. The more degrees of freedom N we have, the better the beam synthesis works, and consequently the lower the mutual overlap of PCA modes is. For the LISP scene illuminations, the average mutual overlap is comparable to that of random scene illuminations. We hence conclude that the diversity of the scene illuminations is not a key factor for the extraction of task‐relevant information.The mutual overlap of PCA‐based illuminations, except for very low N and M, this overlap is around 20% and thus insignificant, as expected. For PCA‐based illuminations we have performed beam synthesis to precisely maximize this overlap. We achieve (65.0 ± 1.9)% with N = 64 and (44.1 ± 1.4)% with N = 16. The ability to synthesize the PCA modes is thus very dependent on the number of metamaterial elements, and these results demonstrate that the PCA‐based approach is suitable only for scenarios where N is large. This observation is a further argument for the attractiveness of our approach in applications with very limited aperture size and tunability like automotive RADAR. In fact, since the PCA‐based approach also requires an analytical forward model, one may as well choose the superior performance of our LISP proposal in any scenario where the PCA‐based approach could be employed. Moreover, training with our approach is faster since all weights are optimized simultaneously, as opposed to first solving M inverse design problems and then training the digital weights.Next, we investigate to what extent the scene illuminations overlap with PCA modes. An example of the overlap with the first 25 PCA modes is provided in Figure M = 1 and M = 2. We conclude that the optimal illumination patterns identified by our LISP cannot simply be explained as corresponding to PCA modes, or to be a good approximation thereof, notably for small M. PCA modes do not account for physical layer constraints, nor the task‐specific inner workings of the nonlinear digital layers.The overlap of the LISP illuminations with PCA modes is around 30% and thus notably larger than for random or orthogonal illuminations but also notably lower than what can be achieved if one seeks PCA modes. Interestingly, the maximum overlap with a PCA mode is lower for 7We have demonstrated that integrating the physical layer of a reconfigurable wave‐based sensor into its artificial‐neural‐network (ANN) pipeline substantially enhances the ability to efficiently obtain task‐relevant information about the scene. The jointly optimized analog and digital layers optimally encode relevant information in the measurements, converting data acquisition simultaneously into a first layer of data processing. We considered classification tasks with dynamic metasurface transceivers and observed 10–15% accuracy gains with limited numbers of measurements compared to current paradigms, as well as improved reliability. A thorough analysis of the learned illumination patterns revealed that they cannot be anticipated from outside the ANN pipeline. Further research should now focus on experimental demonstrations with real‐life tasks, and could also consider ways to enhance the robustness to fluctuations in calibration parametersThe authors declare no conflict of interest.The project was initiated and conceptualized by P.d.H. with input from M.F.I. and R.H. The project was conducted and written up by P.d.H. All authors contributed with thorough discussions.Supporting InformationClick here for additional data file.


Pleural infection is an important clinical problem with significant morbidity. In poorly draining complex pleural effusions, the current management favours a less invasive image‐guided placement of smaller bore catheters and adjunctive intrapleural fibrinolysis therapy (IPFT). We describe our experience of using IPFT in three patients with different bleeding risks with complex pleural effusions. The first was a 30‐year‐old with transfusion‐dependent β‐thalassemia with haemoglobin of 7.8 g/dL; second was an 87‐year‐old on dabigatran with haemoglobin of 10 g/dL; and the third was an 80‐year‐old with diffuse large B‐cell lymphoma with haemoglobin of 8.6 g/dL. All three patients received three doses of alteplase and deoxyribonuclease (DNase) without any adverse effects of bleeding and had resolution of the effusion. This case series is an addition to the current literature on the safety of IPFT and we highlight the use of IPFT in patients with low baseline haemoglobin and on anticoagulation therapy. We described three patients with complex pleural effusions who received intrapleural fibrinolysis therapy with different bleeding risks. Empyema and complex pleural effusion cause significant morbidity and mortality in up to 40% of hospitalized patients with bacterial pneumonia . The maiKlebsiella pneumoniae infection. She was started on intravenous meropenem which was de‐escalated to amoxycillin/clavulanate acid based on blood culture sensitivity. Chest radiograph revealed a moderate left pleural effusion  who were at high risk for surgical intervention. All patients were successfully treated with less invasive intervention by IPFT. We still do not know the optimal dosing regimen and protocol for IPFT . The regBleeding risk following IPFT instillation is a concern for many clinicians. Our three patients had mild anaemia and bleeding risk at baseline. One patient was on oral anticoagulant for atrial fibrillation which was withheld prior to IPFT. We suggest anticoagulation to be withheld based on its half‐life. In all our patients, there were no immediate bleeding events and haemoglobin remained static after IPFT in all cases. This demonstrates the safety of intrapleural fibrinolysis in patients with mild anaemia and bleeding risk. Intravenous alteplase has low rates of severe bleeding of 0.5–8.5% , 5, 9.A treatment shift to a less invasive approach with IPFT appears promising with good safety profile. Our case series of complex pleural effusion successfully treated with short‐duration intrapleural alteplase and DNase demonstrates the safety of intrapleural fibrinolysis in patients with bleeding risk and anaemia using our modified regimen of 16 mg alteplase and 5 mg DNase. We believe this can be an alternative regimen in centres with different alteplase formulation.Appropriate written informed consent was obtained for publication of this case series and accompanying images. We received fundamental grant for a study entitled “The Effectiveness of Short Duration High Intensity Intrapleural Alteplase with DNase (Pulmozyme) in the Management of Pleural Infection” which was approved by UKM Ethics Committee (FF‐2020‐008).


Anyone who has spent a considerable amount of time in visual analysis and manual scoring of EEG events of either human or animal long‐term EEG recordings fully understands that the process is not entirely a labor of love. Manual review of large volumes of EEG data, whether for detection of ictal discharges, epileptiform activity, or abnormal slowing, is notoriously time‐consuming, fatigue‐inducing, and frequently inexact. Numerous analytical software programs have been developed over the last several decades to aid visual review of continuous EEG recordings and have contributed significantly to the precision and accuracy of event detection. However, event detection by even the best algorithms remains an imperfect science. The ongoing need to build better analytical “mousetraps” for EEG event capture continues to be a daunting challenge for epileptologists, computer scientists, and basic researchers.A receptor knock‐in mutation that generates ~6 Hz SWDs (absence epilepsy) in the animal. As many are aware, SWDs in rodent models of acquired epilepsy continue to be an active topic of discussion and interpretation.Such a challenge was embraced wholeheartedly by Pfammatter and colleagues.Their efforts began with two of the authors manually scoring 24‐hour unannotated EEG records outside of the EEG training sets for the presence of SWDs—4 from γ2R43Q mice (RQ) and 1 without the mutation but with the same genetic background (RR)—in order to facilitate the development and performance validation of a 2‐stage algorithm. For Stage 1, they constructed a support vector machine (SVM)‐based algorithm, a learning tool used to analyze data and separate groups of events for classification purposes, after being trained with a set of prescribed labels. Importantly, as the authors describe, the boundaries of the classification space are defined by events assigned as support vectors; the location of each event relative to the nearest support vectors can be used for its classification, and the distance from each event to its nearest support vector can be used as a proxy for confidence in its assigned classification. The algorithm first identified 2500 putative SWDs based on frequency‐ and amplitude‐based threshold criteria from 10, 24‐hour EEG records from five animals (3 RQ and 2 RR). From these 2500 presumed SWD events, 2050 unique events were randomly chosen, from which 50 events were selected to be randomly repeated 10 times each. Combining these events together, a new set of 2500 SWD events was presented to four experienced reviewers, including an epileptologist, to score the detections as SWD or non‐SWD. In so doing, intra‐ and interrater scoring consistencies could be calculated.From the putative events detected by Stage 1, 12 predictor variables were extracted for use in Stage 2 of the algorithm, intended to classify events with an SVM. Using a wavelet transform of each event and targeting the typical frequency of SWDs in mice and several of its harmonics, the 12 predictor variables were calculated from four frequency bands using the mean, standard deviation, and maximum value for each event. Together with the results of the human scoring, the SVM was trained to classify each event as either SWD or non‐SWD and assigned confidence scores to each event.Event detection in EEG recordings by expert reviewers runs along a spectrum of difficulty depending on the nature of the event. For example, ictal discharges in human EEG recordings that demonstrate “classical” findings such as an abrupt low‐voltage/high‐frequency discharge followed by evolving changes in amplitude and frequency and post‐ictal slowing usually can be recognized without much difficulty. Accurate identification of epileptiform activity, or pathological slowing versus that of variable drowsiness, becomes an entirely different matter. The same challenge is no less true when trying to identify SWDs in animal EEG recordings. Although SWDs are commonly found in both inbred and outbred rodent strainsExpert review of EEG tracings is a critical component of the training and validation of an algorithm for event detection and is considered a “gold standard” in investigations.In summary, Pfammatter and colleagues have produced an exceptional report that contributes substantially not only to the study of rodent SWDs but potentially more broadly to experimental studies of acquired epilepsy and studies focused on EEG event detection in various clinical settings. They are commended for their efforts.I have no conflicts to disclose. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.https://onlinelibrary.wiley.com/doi/abs/10.1002/epi4.12303Read the winning article ‐


Oncorhynchus mykiss), whereas lineage UC displayed a generalist phenotype across steelhead trout, rainbow trout, and Chinook salmon. Furthermore, our results suggest the presence of specialist–generalist trade‐offs because, while lineage UC had moderate probabilities of infection across host types, lineage MD had a small probability of infection in its nonadapted host type, Chinook salmon. Thus, in addition to quantifying probabilities of infection of socially and economically important salmonid hosts with different IHNV lineages, our results provide insights into the trade‐offs that viral lineages incur in multihost communities. Our results suggest that knowledge of the specialist/generalist strategies of circulating viral lineages could be useful in salmonid conservation programs to control disease.Many pathogens interact and evolve in communities where more than one host species is present, yet our understanding of host–pathogen specialization is mostly informed by laboratory studies with single species. Managing diseases in the wild, however, requires understanding how host–pathogen specialization affects hosts in diverse communities. Juvenile salmonid mortality in hatcheries caused by infectious hematopoietic necrosis virus (IHNV) has important implications for salmonid conservation programs. Here, we evaluate evidence for IHNV specialization on three salmonid hosts and assess how this influences intra‐ and interspecific transmission in hatchery‐reared salmonids. We expect that while more generalist viral lineages should pose an equal risk of infection across host types, viral specialization will increase intraspecific transmission. We used Bayesian models and data from 24 hatcheries in the Columbia River Basin to reconstruct the exposure history of hatcheries with two IHNV lineages, MD and UC, allowing us to estimate the probability of juvenile infection with these lineages in three salmonid host types. Our results show that lineage MD is specialized on steelhead trout and perhaps rainbow trout (both  Then, by assuming a homogeneous lineage identity, we test for differences in the probability of infection of different hosts  given that exposure occurs by the same host compared to when it occurs by other hosts (using a host model). Lastly, we test whether the probability of infection of the three host types depends on the lineage to which they are exposed (using a host‐by‐lineage model). Given exposure to pathogens, specialized lineages should pose a higher risk of infection to the host to which they are specialized, whereas generalist pathogens should pose an equal risk of infection across hosts. Therefore, given exposure, differences in a lineage's probability of infection across different hosts should indicate whether pathogen lineages are specialists or generalists.22.1We developed three models to estimate the probability of juvenile infection given exposure to IHNV across 13 cohorts (sampled from 2000 to 2012) at 24 hatchery sites located in the Columbia River for a total of 312 cohort‐sites Figure . A cohorMissing test records  in juveniles and adults occurred in 37.5% and 27% of cohort‐sites, respectively  using a multiple imputation procedure  were calculated after verifying that values of the Gelman–Rubin potential scale reduction factor (R‐hat), which suggests chain convergence, were between 1 and 1.02 , missing data due to no testing but complete genotyping of positive tests (Scenario 2), and missing data due to no testing and incomplete genotyping of positive tests  across the cohort‐sites, without including the effects of host identity. This model allowed us to determine whether the probability of infection with the three lineages can be precisely estimated to help interpret the final host‐by‐lineage model (which contains a large number of parameters). We expect to obtain precise estimates of the probabilities of infection with lineages UC and MD and low precision for the probability of infection with lineage UP. This is because lineage UC is often detected across several salmonid hosts and lineage MD is frequently detected in steelhead and rainbow trout. By contrast, lineage UP is only rarely observed in the studied hatcheries.ϵ) and the probabilities of infection with a particular lineage given no genotyping of positive tests  were inferred as described above under “Section ρ1, ρ2, and ρ3), the model considered whether each of the three routes exposed a cohort‐site to a lineage ; hence, a cohort‐site could be exposed a maximum of three times. We then estimated the probability of infection with each lineage given exposure using Bernoulli likelihoods and vague priors ).If the cohort‐site was not tested or was positive but not genotyped, then the probability of juvenile infection given no test  were tested in cohort t − 1. Similarly, adults were assumed to be present at the site in cohort t if juveniles of the same host type were tested at the site in cohort t + 1. If no records for either adults or juveniles were found in cohort t or t + 1, respectively, we assumed that the host type was absent from both cohorts of the site  was calculated as:Under this model, a cohort‐site could have been exposed to IHNV a maximum of six times . Thus, the probability of infection of host s is either Chinook salmon, steelhead trout, or rainbow trout; ϕ is the probability of infection when exposed by the same host; and θ is the probability of infection when exposed by other host types.Here, 2.7In the host‐by‐lineage model, we estimated the probability of infection for the three salmonid hosts with lineages MD and UC. We excluded lineage UP from this model because only one positive test for this lineage was recorded among all cohort‐sites, and including this lineage in the model would add 12 parameters, which would likely increase estimation uncertainty. We expect to see evidence for specialization of lineage MD on steelhead and rainbow trout by the probability of infection with MD being greater in these hosts compared to Chinook salmon. By contrast, we expect to see similar probabilities of infection with lineage UC across salmon hosts, which would be consistent with the generalist phenotype suspected for this lineage  of salmon host s given exposure with lineage l as:In this model, a cohort‐site could be exposed a maximum of 12 ways, for example, if the three hosts were exposed to the two lineages by the same and other host types. We thus calculated the probability of infection sα,l is the probability of infection when exposed by the same host, and sβ,l is the probability of infection when exposed by other host types, such that sα,lβs,l is the probability of infection when exposed by the same and other host types.Here, 33.1Simulation results from the lineage model confirm that missing data have an effect on parameter estimation. Nevertheless, even with missing tests  than the probability of infection with lineage UC (median estimate = 0.09), despite exposure to UC occurring most often Figure . The pro3.2Simulation results showed evidence of underestimation for the probability of infection given exposure by other host types when the true value of the probability of infection given exposure by the same host was greater than approximately 0.5 , because of high probabilities of infection given exposure, and not adapted to Chinook salmon, because of near‐zero probabilities of infection given exposure. Furthermore, in steelhead trout, we found that the probability of infection with lineage MD was highest when infected steelhead trout were the source of exposure, as opposed to other host types . Finally, the host‐by‐lineage model showed that lineage MD appears specialized on steelhead and rainbow trout , which could lower juvenile mortality caused by high‐virulence specialized lineages compared to low‐virulence generalist lineages. As an example, successful reduction in juvenile mortality from infection with MD genotypes resulted from a management action that avoided exposure of juvenile steelhead trout to river water containing adult steelhead trout in the Dworshak hatchery  . Thus, expanding these modeling efforts to include hatcheries along the Snake River where lineage UP and sockeye salmon are more prevalent may allow for precisely quantifying probabilities of infection with lineage UP. Similarly, we were unable to make precise inferences about the probability of infection of rainbow trout due to data limitations. In our study area, fewer hatcheries reared rainbow trout , and they were nearly always reared with other species. In addition, hatchery production of rainbow is aimed at restocking inland lakes for recreational fishing. This removes the effect of adult‐to‐juvenile exposure because adult rainbow trout do not migrate back to the hatchery. Additional data across more hatcheries may thus be needed to precisely estimate the probability of infection of this host type.Assessing the risks that diseases impose on fish is an important step in preserving the health of managed wildlife. Previous studies have developed mechanistic SIR‐type models to propose mechanisms that explain disease dynamics in other fish host–pathogen/parasite systems (Boerlage, Graat, Verreth, & Jong, None declared. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


To describe the clinical outcomes of occipitocervical fusion (OCF) using cervical pedicle fixation with assistance of O‐arm navigation and present its clinical feasibility.From January 2015 to December 2016, eight patients with a variety of diagnoses were surgically treated with occipitocervical fusion using cervical pedicle screws under O‐arm navigation. All patients received full workup consisting of clinical and radiological assessments. Perioperative parameters including operating time, intraoperative blood loss, postoperative complications, surgical outcomes were recorded. Postoperative data were acquired resorting to the scheduled follow‐up 3, 6 and 12 months after their discharge and annually afterwards. The Japanese Orthopaedic Association (JOA) Scores and American Spinal Injury Association (ASIA) Scale were used to evaluate neurological function. The accuracy of screw placement was classified according to a modified classification of Gertzbein and Robbins. The fusion status was evaluated in reference to the Bridwell's posterior fusion grades.The patient cohort comprised of five males and three females, with the average age of 51.9 years (range from 18 to 74 years). The patients all showed indications for OCF and were performed with polyaxial screws through cervical pedicles. The average operation time was 274 min (range from 226 to 380 min), with the intraoperative blood loss of 437.5 mL and the blood transfusion volume of 481.3 mL. The average follow‐up time was 23.5 months (range from 17 to 32 months). All patients exhibited radiographic evidence of osseous fusion by X‐ray and computed tomography (CT) at the final follow‐up. No neurovascular complications were found during the follow‐up time, and the clinical symptoms were observed to be significantly improved in all the patients. Thirty‐four cervical pedicle screws were implanted within the eight patients, with the accuracy of cervical pedicle screw placements as 94.1% (32/34), among which, two pedicle screws were found to broken through the cervical pedicles that were evaluated as Grade II.Occipitocervical fusion via cervical pedicle fixation assisted with O‐arm navigation is a feasible and safe procedure with a vast range of indications. Occipitocervical fusion (OCF) is used to treat craniocervical pathologies losing biomechanical stability. These disorders generate clinical symptoms, including severe occipital neck pain, restricted neck movement, myelopathy, which significantly reduce patients' quality of life. Traumatic dislocation or subluxation, congenital malformation, craniovertebral junction (CVJ) reconstruction after decompression are the most common indications of occipitocervical fusionHowever, traditional surgical technique guided with C‐arm fluoroscopy is challenging and vulnerable to damage vertebral artery, spinal cord, or nerve root. These iatrogenic injuries might lead to intraoperative massive hemorrhage, cardiopulmonary arrest, high paraplegia, or paralysis. Recently, several studies have reported that O‐arm navigation is a safe, feasible, and efficient application in lumbar surgeriesIn this study, the results of treatment were evaluated by retrospective follow‐up of patients: (i) to evaluate the accuracy of screw placement under O‐arm navigation; (ii) to observe the fusion status after operation; and (iii) to assess the clinical outcome of occipitocervical fusion using cervical pedicle fixation under O‐arm navigation.This retrospective study reviewed eight patients performing occipitocervical fusion in our institution between January 2015 and December 2016. All patients were operated with occipitocervical fusion using cervical pedicle screws under O‐arm navigation by the same surgical team. All patients received full workup consisting of clinical and radiological assessments. Perioperative parameters including operating time, intraoperative blood loss, postoperative complications, surgical outcomes were recorded. Postoperative data were acquired resorting to the scheduled follow‐up 3, 6, and 12 months after their discharge and annually afterwards. Inclusion criteria were as follows: (i) patients with instability of craniocervical lesions; (ii) occipitocervical fusion via cervical pedicle fixation assisted with O‐arm navigation; (iii) comparison of preoperative and postoperative status; (iv) evaluation of surgical procedure and postoperative status; and (v) retrospective study. Exclusion criteria were as follows: (i) lost to follow‐up; (ii) infections, psychiatric disorders, coagulation disorders; and (iii) cancer patients.The highest score of JOA is 29, and the lowest is 0. Improvement rate = [(post‐treatment score − pre‐treatment score)/29 − pre‐treatment score] × 100%. The clinical treatment effect can be understood by the improvement rate. When the improvement rate is 100%, it is a cure. When the improvement rate is more than 60%, it is significantly effective. When the improvement rate is 25%–60%, it is effective. When the improvement rate is less than 25%, it is ineffective.American Spinal Injury Association (ASIA) Scale was used to evaluate neurological function. A = Complete: No motor or sensory function is preserved in the sacral segments S4‐S5. B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4‐S5. C = Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3. D = Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more. E = Normal: motor and sensory functions are normal.The accuracy of screw placement was classified according to a modified classification of Gertzbein and RobbinsThe fusion status was evaluated referring to the Bridwell's posterior fusion gradesOur study protocol was approved by the Ethics Review Committee of the Institutional Review Board of the hospital. All the patients or families are informed of standard written consent to acquire their clinical information. This case series study has been reported in line with the PROCESS criteriaUnder general anesthesia, the patients were placed in the prone position with their head fixed in slight flexion with head holder.2 and C3 vertebrae were exposed for placement of the pedicle screws by blunt dissection.A conventional midline incision was made from external occipital protuberance (EOP) to spinous process of the third cervical vertebrae. The posterior components were exposed using the classic subperiosteal technique with great caution to avoid injuring the greater occipital nerve. The facet joints of the C2 and C3 and another four screws were placed on both sides of EOP, below the superior nuchal line.The posterior arch of the C1 vertebrae was exposed for adequate decompression or as a salvage backup to provide pedicles for fixation when indicated. Under O‐arm navigation, the entry point and orientation of the screws were adjusted to conform to the complex anatomy of cervical pedicle. Four screws were inserted strictly in place through the pedicles of CAfter attaching two pre‐bent connecting rods to screws bilaterally, a final scan was conducted to evaluate the position of implantations, intraoperative reduction and/or decompression. A high‐speed grinder was used to polish posterior cortex of the occipital bone and cervical lamina whereupon bone grafting was performed.According to the individual condition of each patient, prolonged segment fusion, deformity correction, C1 posterior arch excision, or laminoplasty was performed.The demographic features and clinical information for these patients are summarized in Table The symptoms of the patients were improved and the surgical treatment was effective Table . The impNo neurovascular complications occurred, and the clinical symptoms had improved for all patients Table . Three pIn all, thirty‐four cervical pedicle screws were implanted. The distribution and the accuracy grades of the screws were list in Table 5. The accuracy of cervical pedicle screw placements was 94.1%(32/34). Two pedicle screws were observed penetration less than 2mm and considered as Grade B.All patients exhibited radiographic evidence of osseous fusion by X‐ray and CT reconstruction at the final follow‐up. X‐ray and CT showed that the sequence of vertebral body was good. No pseudarthrosis and displacement in the vertebral body of all patients and no loosening or fracture of screws were found.1 posterior arch and C2 spinal process was slightly expanded and the odontoid process presented as a dorsal arch shape. Dynamic plain radiographs showed no signs of instability or dislocation/subluxation. The CT scan further confirmed the radiological changes above. Notably, we defined the pedicles of C2 as unsuitable working cannels according to scans on transversal plane , accompanied by tendon hyperreflexia. During the course of disease, no history of traumatic injury was acknowledged. Preoperative X‐ray indicated a mild deformity in the atlantoaxial joint, the interval between C7 was made to perform the hybrid surgery‐OCF integrated with laminoplasty. We did the fixation from EOP to C4, while the C2 pedicles were rechecked intraoperatively to be bypassed, instead we maneuvered the fixation through pedicles of C1. The occipital bone was partly bit off with the rongeur till the medulla is exposed for sufficient decompression, accompanied by laminoplasty from C3 to C7. Three micro plates were attached to the open door of C3, C5, and C7 to prevent from recurrence of stenosis  O‐arm provides three‐dimensional reconstructed views of the patient as currently positioned on the operating table and the concern of navigational inaccuracy due to differences in intervertebral alignment between a preoperative image and the intraoperative position is obviated; (ii) the scan was performed only once, which reduces radiation exposure and fluoroscopy time, and as all the staff would leave the operation room in advance, there was nearly no hazard to surgeons; and (iii) O‐arm could interface seamlessly with the Navigation System compared with the three‐dimensional C‐arm fluoroscopy, which could eliminate the time of registration and transferring acquired scans.et al. reported a misplacement rate as low as 5% to 6.7% with the help of O‐arm navigation1 pedicle screw placement in clinical practice2 pedicles revealed that bilateral pedicles were obviously narrow, then two screws were inserted through C1 pedicles respectively. In another patient, two C1 pedicle screws were inserted for the same consideration. All the four C1 pedicle screws were critically positioned within the osseous channels with Grade I. Combined with this experience, we deem that the pedicles of the upper cervical should not always be regarded as the forbidden area. Pedicle fixation of upper cervical spine, including the atlas, is feasible with the assistance of O‐arm navigation and is worth being promoted for better biomechanical performance.With guidance of real‐time navigation, surgeons completed all the fixations via cervical pedicle and obtained a favorable accuracy of screw placement. Patients in the present study were frequently accompanied by severe hyperosteogeny due to degeneration, or instability generated from congenital deformity, which increased the difficulty of placing the cervical pedicle screws. The O‐arm provided us the trajectory of screws by setting parameters including the diameter and length, meanwhile, a virtual screw was computed, displaying on reconstructed images. All the screw placements and revisions were performed under direct orientation without the need to rely on bony landmarks. Former studies reported a quite high breach rate ranging from 16.9% to 23% using freehand techniqueMany factors are related to surgical complications, such as the type of instrumentation, underlying pathology, the clinical experience of operator and postoperative treatment. The overall rate of postoperative adverse events was reported to be 52%, among which neurological deterioration accounted for 41% and wound complications such as infection and dehiscence accounted for 30.9%This surgical procedure also has good compatibility with other operations. Two cases successfully underwent hybrid surgeries in this study and internal instrumentations did not interfere with each other. Various means of decompression were employed under the support of solid internal fixation. By resorting to the final scan, surgeons had the opportunity to make assessment and correction in the same operative setting. Besides, in terms of operation time, our result is comparable to other surgical procedures performing OCFThere are several limitations in our study. First, sample size is small, which is related to the extremely rare and rigorous conditions. Second, this case series aims to provide primary experience so that no group was set for comparisons. Our results will need to be confirmed in larger series and using study design with higher level evidence.This retrospective case series demonstrates that O‐arm navigation assisted OCF using cervical pedicle fixation is a feasible and safe procedure with a vast range of indications. The O‐arm navigation greatly improves the accuracy of screw placement and makes it possible to gain better biomechanics in CVJ without sacrificing clinical outcomes. Further study containing larger samples was required to provide higher evidence regarding its clinical practice.Yes.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


In the setting of an infected prosthetic ascending thoracic aorta, prompt and definitive surgical treatment is mandatory to avoid catastrophic bleeding complications. In the setting of an infected prosthetic ascending thoracic aorta, prompt and definitive surgical treatment is mandatory to avoid catastrophic bleeding complications. A 69‐year‐old female transported to the emergency department with class IV hemorrhagic shock. Ambulance paramedics found her lay down lethargic covered by severe amount of blood. The patient underwent ascending aorta replacement 2 years prior to a Stanford A acute aortic dissection complicated by deep sternal wound infection including a chronic draining sinus tract and an aorto‐cutaneous fistula at the upper body sternum developed 1 year and 3 months prior, respectively. During resuscitation, external opening compression sutures of the aorto‐cutaneous fistula placed, and the patient stabilized and underwent whole‐body CT with no evidence of free aortic rupture, as shown in Figure 1According to family, the patient performed a heavy weight lift before exhibiting oozing blood from the aorto‐cutaneous fistula. As there was no adequate patient and family education, local bleeding management by firm pressure to the external opening was not performed resulting in severe hemorrhage. The Valsalva maneuver that the patient performed for weight lift resulted in transient aortic pressure increase which normally has no significant impact. However, in the setting of an infected prosthesis combined with false aneurysm and aorto‐cutaneous fistula, transient significant aortic pressure increase led to aortic rupture.The authors declare that they have no conflict of interests.All authors equally accessed the data and contributed to the preparation of the manuscript. TA and HA: responsible for making and performing treatment decisions. HA: reviewed the manuscript for critical intellectual content and had the final approval.Informed consent was obtained from the patient.The present article does not contain any studies with human or animal subjects performed by any of the authors.


The non‐covalent affinity of photoresponsive molecules to biotargets represents an attractive tool for achieving effective cell photo‐stimulation. Here, an amphiphilic azobenzene that preferentially dwells within the plasma membrane is studied. In particular, its isomerization dynamics in different media is investigated. It is found that in molecular aggregates formed in water, the isomerization reaction is hindered, while radiative deactivation is favored. However, once protected by a lipid shell, the photochromic molecule reacquires its ultrafast photoisomerization capacity. This behavior is explained considering collective excited states that may form in aggregates, locking the conformational dynamics and redistributing the oscillator strength. By applying the pump probe technique in different media, an isomerization time in the order of 10 ps is identified and the deactivation in the aggregate in water is also characterized. Finally, it is demonstrated that the reversible modulation of membrane potential of HEK293 cells via illumination with visible light can be indeed related to the recovered trans→cis photoreaction in lipid membrane. These data fully account for the recently reported experiments in neurons, showing that the amphiphilic azobenzenes, once partitioned in the cell membrane, are effective light actuators for the modification of the electrical state of the membrane. The use of light to achieve control of cellular signaling is an important topic in pharmacology. Here, it is shown that an amphiphilic azobenzene performs ultrafast isomerization when partitioned into the cell membrane, while in water its photoisomerization ability is lost because of the formation of excimeric aggregates. This enables fast and reversible modulation of the membrane potential. The precise, fast, and efficient spatiotemporal control of cellular signaling via the use of external triggers has become an important topic in chemical biology[qv: 1] and photopharmacology. In this regard, light‐responsive systems offer the possibility to employ light as a clean, non‐invasive, and spatio‐temporally precise tool for controlling a variety of biological signals both in vitro and in vivo.[qv: 4–9] A plethora of photochromic systems allowing modulation of molecular responses in a reversible fashion have been developed. Among them, azobenzenes[qv: 12] are widely employed as versatile photoresponsive element for conferring reversible sensitivity to bio(inspired) targets and drugs, such as artificial membranes,[qv: 13–15] peptides, nucleic acids, ion channels, living organisms,[qv: 22] and antibacterial molecules.[qv: 23–25] These studies have demonstrated that effective and reversible photomodulation can be achieved both in vitro and in vivo, by the covalent binding of the azobenzene unit to the selected target. Alternatively, one can exploit non‐covalent interactions to assist the incorporation of photoactive molecules in bio‐systems.[qv: 26–30] Although this method is less specific than the covalent approach, the relatively weak non‐covalent interactions still allow for driving affinity to various bio‐interfaces, while ensuring full reversibility and much lower invasiveness. For instance, the ability of amphiphilic azobenzenes to intercalate spontaneously in model artificial membranes and micelles has been used to guide their internalization into these systems, mostly to study intrinsic membrane properties, to build up photoresponsive cargos for drug delivery applications, or to provide novel antibacterial systems.[qv: 25] Very recently a new amphiphilic azobenzene molecule named ZIAPIN2 has been introduced. ZIAPIN2 predominantly localizes in the plasma membrane and potently modulates neuronal firing in vitro as well in vivo via an opto‐mechanical effect.[qv: 34] In order to fully characterize the photostimulation mechanism of ZIAPIN2, here we report a detailed investigation of its photophysics and dynamics in different media. By combining steady‐state and time‐resolved optical spectroscopies, we observed that ZIAPIN2 in water lends itself to a radiative transition likely mediated by the formation of excimers, whereas it reacquires its conformational dynamics in membrane‐mimicking environments. Characteristic time scales and reaction yields are reported, reconciling the fast response (ms) observed in functional studies and the apparent slow ensemble evolution(s) by determining the molecular conversion time in the tens of picosecond range. Finally, we validate this opto‐mechanical phenomenon in a non‐excitable cell line that has an intrinsically low concentration of ion channels, to single out the effect on the plasma membrane itself.Figuref = 1.33) featuring an n–π* character with molecular orbitals delocalized over the azobenzene moiety. The cis species shows two vertical dipole active excited states computed at 537 nm (f = 0.18) and 367 nm (f = 0.33), associated with the n–π* and π–π* transitions, respectively. Note that the diamino substitution induces a red shift of the optical gap with respect to the unsubstituted azobenzene that is favorable to biological applications. As discussed in the following sections, the addition of water induces a broadening and a red‐shift of the absorption spectrum of the trans species. To a first approximation, we performed DFT/conductor‐like polarizable continuum model calculations on the single molecule. Considering water as a solvent, two active states are computed at 456 nm (f = 1.34) and 436 nm (f = 0.15), the former being red‐shifted by 26 nm with respect to the active state in the vacuum case. We preliminary speculate that such a shift in the ground state absorption might be related to the solvent cage (in this case water) that can play a role in the molecular conformation. As shown later, however, modeling at the single molecule level is not sufficient to fully account for the observed phenomena.ZIAPIN2 was synthesized by reduction of the commercially available Disperse Orange 3 followed by the substitution of the amines with an excess of 1,6‐dibromohexane. Full details about the synthesis can be found in ref. We used UV–vis absorption and photoluminescence (PL) spectroscopies to investigate the behavior of ZIAPIN2 in the following media: i) DMSO that is a good solvent, as a control medium and vector for ZIAPIN2; ii) water that is the main component of extracellular and intracellular media; and iii) micelles of sodium dodecyl sulfate (SDS) to mimic the lipid bilayer environment.[qv: 34–36] The latter is useful for steady‐state and transient absorption measurements (vide infra) that are difficult to perform in intact cells. We selected SDS as it spontaneously forms mixed micelles upon combination with single‐tailed surfactants with oppositely charged head groups. In the UV–vis absorption spectra Figure , we obseFigurem, and water . In water  indicate that the photoinduced PL quenching occurs almost totally in the membrane region, while residual ZIAPIN2 molecules present in the aqueous extracellular buffer do not seem to undergo isomerization. This confirms that lipid environment allows restoration of ZIAPIN2 photoswitching ability.Steady‐state absorption measurements of ZIAPIN2 in solution under an actinic light allow the assessment of the ensemble dynamics of isomerization. In r Figure ,d,f. In r Figure ,b, we obr Figure , in goodr Figure ,f, ZIAPIr Figure ,d, howevFigure0→S*, PB); ii) another positive peak at 570–610 nm that can be linked to stimulated emission , and iii) a negative feature at around 700 nm due to photoinduced absorption from excited states . To obtain quantitative insights into the complex convolution of the trans and cis spectra, we employed a global analysis algorithm. We describe our experimental data with two components  and the experimental value (0.12) for ZIAPIN2 in water  confirms the kicking in of a different deactivation mechanism in the aqueous buffer. We assign the breakdown of the Strickler–Berg rule to the formation of an aggregate excited state, possibly an excimer, with higher radiative rate. The findings in SDS are consistent with our steady‐state spectroscopic data and suggest that ZIAPIN2 performs ultrafast isomerization reaction in membrane. The tiny changes observed in the ensemble measurements in SDS/cells are likely due to the presence of a mixed population in which only a fraction of ZIAPIN2 molecules is protected by water.In electrophysiology experiments, neurons reacted to short burst of light, between 20 and 200 ms. The prompt response seems in contradiction with the time evolution measured in solution, taking place in seconds. One should however notice that steady‐state measurements allow accessing the isomer fraction population in the ensemble. In order to gain insights into the molecular isomerization event  it is necessary to employ ultrafast techniques.[qv: 46] We carry out a transient absorption (TA) experiment where a pump pulse brings population to the excited state, while a broadband probe pulse interrogates this state and tracks its temporal evolution. With this technique, we studied the ZIAPIN2 photodynamics in the three media of choice, namely water, DMSO, and SDS. The TA spectra at early delay‐times  in HEK293 cells, which represent a well‐established cellular model. Possible cytotoxicity of ZIAPIN2 was evaluated by using the Alamar Blue standard test, which indicates that exposure to ZIAPIN2 does not have an appreciable impact on cell proliferation . We measured the light‐induced change in the resting plasma membrane potential (Vm) by applying the patch‐clamp technique in current clamp mode (I = 0) . In agreement with what has been found in neuronal cells,[qv: 34] photostimulation of ZIAPIN2‐loaded HEK293 cells with either short (20 ms) or long (200 ms) visible light pulses  also generated a significant hyperpolarization of Vm that appeared immediately at the light onset and slowly returned to the physiological resting values after a slight rebound depolarization phase after the light offset . In our previous study, we have assigned this potential modulation to a photoinduced thinning/thickening of the cell membrane leading to an increase/decrease of the membrane capacitance.[qv: 34] To link ultimately such an effect to the ZIAPIN2 ultrafast photoreaction occurring in the membrane environment, we therefore recorded the |ΔVm| of hyperpolarization and depolarization as a function of the illumination wavelength for 20 and 200 ms light stimulation  with non‐covalent affinity for cell membranes can act as an efficient, fast, and reversible modulator of the membrane potential via visible light. By applying steady‐state and time‐resolved ultrafast spectroscopies, we note that in water a strong aggregation occurs, effectively hampering photoisomerization and opening up a deactivation path likely mediated by excimer formation. Alternatively, internalization in the cell membrane prevents self‐aggregation and restores the intrinsic ultrafast response of the photo switch. This, ultimately allows light‐triggering a large hyperpolarization in HEK293 cells whose magnitude follows the absorption profile of the trans state in membrane and, remarkably, permits evoking biological photoinduced effects in vivo.[qv: 34] Such actuators are new tools that could contribute to the development of opto‐neuroscience, biophotonics, and photopharmacology.The authors declare no conflict of interest.Supporting informationClick here for additional data file.


Birt‐Hogg‐Dubé syndrome (BHDS) is an extremely rare genetic condition that predisposes to renal cell carcinoma. This case describes a novel case of a patient with BHDS who also develops follicular thyroid cancer. Birt‐Hogg‐Dubé syndrome (BHDS) is an extremely rare genetic condition that predisposes to renal cell carcinoma. This case describes a novel case of a patient with BHDS who also develops follicular thyroid cancer. BHDS is a rare hereditary cancer syndrome, which predisposes to renal cancer, pulmonary cysts, and cutaneous fibromas. This case provides a novel account of an unexpected malignancy in an extremely rare disease.A 45‐year‐old woman was detected to have bilateral renal masses on computed tomography (CT) (2 cm in diameter left and 3.6 cm in diameter right) when being investigated for lower abdominal pain  gene. Results from this testing were unable to confirm a diagnosis of BHDS. Nevertheless, it was recommended her sons receive screening with renal tract ultrasound from age thirty, every five years. The patient remained stable for two years, receiving thrice‐weekly hemodialysis at a satellite unit.The following year, the patient was referred for genetic counseling to consider whether the occurrence of bilateral renal tumors was secondary to a genetic disorder. During this consultation, it was noted on examination that she had multiple skin tags on her neck and chest. The patient was tested for the Birt‐Hogg‐Dube syndrome (BDHS) with genetic testing for the disease‐causing variant in the 2The patient was subsequently considered for renal transplantation. Her case was reviewed by a team of specialist renal transplant physicians and surgeons, and it was recommended she undergo a nephrectomy to remove remaining renal tissue to minimize the risk of future malignancy. The surgery was complicated by splenic capsular tear, left adrenalectomy, and partial pancreatectomy. She suffered severe hypovolemic shock which required resuscitation in the intensive care unit but recovered and was later discharged following a prolonged admission to continue ongoing regular hemodialysis.folliculin gene in exon 14. Based on this information, a formal diagnosis of BHDS was made.Additional investigations were undertaken to assess the patient for renal transplant. CT of the chest demonstrated bilateral pulmonary cysts. These cysts were asymptomatic and associated with normal lung function testing. Specialist respiratory and surgical opinions were sought, and no intervention was advised as the risk of pneumothorax was deemed low. Further genetic testing undertaken using multiplex ligation–dependent probe amplification testing in Germany revealed a deletion in major functional parts of 123 scan did not demonstrate residual thyroid tissue in the neck.During an outpatient clinic appointment, a large left thyroid nodule was found on examination. Ultrasound‐guided fine‐needle aspiration of the mass demonstrated highly atypical epithelial proliferation, suspicious for thyroid follicular neoplasm. She had a total thyroidectomy and left neck dissection to remove a 60 mm, poorly differentiated follicular thyroid carcinoma. The patient was treated with liothyronine tablets, and an I3Six months following her surgery, the patient reported severe back pain. CT showed multiple nodules throughout the lungs and lytic lesions in T8 and T12 vertebra  gene of which >150 disease‐causing variants have been discovered.Birt‐Hogg‐Dubé syndrome an extremely rare autosomal dominant condition caused by a germline mutation in the tumor suppressor FLCN gene mutation is diagnostic of BHDS, it is not essential as clinical criteria may be used.Renal cell carcinoma is uncommon and usually attributable to sporadic synchronous renal cell carcinoma, as only 2%‐5% of renal cell carcinomas are believed to be inherited.(2016) described two patients with BHDS who developed bilateral and multifocal papillary thyroid cancer. It was postulated that for patients with BHDS and thyroid cancer, total thyroidectomy with central neck dissection may be suitable as it is possible that there is a tendency for more extensive and severe thyroid disease.There are reports of thyroid cancer in patients with BHDS Patients with hereditary cancer syndromes who are being considered for solid organ transplantation require extensive screening and surveillance for malignancy to avoid devastating outcomes.This case illustrates the complexity in managing a patient with a severe phenotypic presentation of BHDS. While there is no causal association that can be drawn on the basis of this case between thyroid cancer and BHDS, the case does support the notion proposed by Dong et al (2016) that aggressive treatment of thyroid cancer in this patient group may be considered. Moreover, for patients with BHDS being considered for renal transplantation, an awareness of reports of thyroid cancer in this patient group may prove invaluable.No conflicts of interest to declare.EKB: oversaw the synthesis of the manuscript and review of relevant literature. RR: made significant contribution toward editing of the manuscript. DC: made significant contribution toward editing of the manuscript. MM: made significant contribution toward editing of the manuscript.


This study examines how the receipt of the cash‐for‐care (CFC) benefit affects short‐ and long‐term risks of union dissolution.Several theories predict that couples' gendered division of labor decreases their risk of separation, either due to increased partnership satisfaction or because it establishes economic dependency. Family policies such as the Finnish CFC benefit, which is paid if a young child does not attend public daycare, may encourage such a gendered division of labor, at least temporarily.Using Finnish register data, this study analyzes the first childbearing unions of 38,093 couples between 1987 and 2009. Discrete‐time event history analyses and fixed effects models for nonrepeated events are applied.The results suggest a lower separation risk while the benefit is received as compared to couples who do not use it, but no effect in the long‐term. Fixed effects models that control for selection into CFC indicate postponement of separation until after take‐up. Higher‐income mothers show a stronger postponement effect, possibly due to greater income following leave.CFC use, which signals a temporary gendered division of labor and losses in mothers' earnings, predicts a lower separation risk during receipt of the benefit, but not beyond.Policies that affect the division of paid and unpaid labor at best only temporarily reduce dissolution risks. Family policies have various aims, such as the promotion of maternal employment, enhancing the compatibility of family life and paid work, gender equality, child development, and poverty reduction  benefit in Finland influences the risk of separation. CFC is paid to parents of children under the age of three who are not in publicly provided childcare, and is primarily used by mothers to care for their children full time. CFC therefore decreases the labor supply of mothers of young children , by comparing EHA estimates with those from fixed effects models for nonrepeated events , monthlOur analytical sample consists of unions of Finnish‐born women in which they had their first biological child. The data covers the years from 1987 to 2009, and the couples entered the data between 1988 and 2007, that is, during the years in which we could observe their first births and their CFC use. On average we follow these couples for 6.3 years, all of the couples were eligible to receive CFC. The analyses included 38,093 couples of which 9,014 separated, contributing 312,256 couple‐years at risk.The dependent variable is the dissolution of the woman's first childbearing union in a given year—defined as partners permanently moving apart or divorcing, whichever came first. Because families become eligible for CFC once the child is 9 months old, and because we lag the CFC use variable by 1 year (see below), the couples become at risk of union dissolution on the second calendar year after the first child is born. The unions are right‐censored if the woman emigrates, either partner dies, or at the end of the observation period (September 2009).Our main independent variable is a time‐varying measure of CFC use and time since the latest use. The variable is lagged (by 1 year) to avoid confusing the time‐ordering of CFC receipt and separation. This variable is based on annual data of the received amount; we do not have information on the exact duration of the CFC use in a given year. Therefore, for the main analysis, the time‐varying CFC use variable includes the following categories: no previous CFC use (reference category), current CFC use, 1 year since, 2–4 years since, 5–7 years since, and 8+ years since the latest CFC receipt. Categories indicating years since the latest use were included to estimate whether CFC use affects the union dissolution risk beyond the take‐up.We included three groups of control variables. The first comprises duration (linear and squared), period  in groups based on economic cycles, and union duration at the birth of first child (in years). The second group includes variables measuring the couple's sociodemographic profile: age  in 10‐year age groups (time‐varying); education of both partners (time‐varying), categorized as basic, secondary vocational, secondary academic, lower tertiary, and higher tertiary; union type prior to first birth (marriage or cohabitation); region of residence (time‐varying), differentiating urban, semiurban and rural municipalities; the number of months the mother had been employed the year prior to the first birth; partners' unemployment (time‐varying dummy), and mother's income prior to first birth deflated to the euro value in 2011, collapsed in the following categories: less than 10,000, 10,000–15,999, 16,000–27,999, more than 28,000. Third, because CFC receipt is tied to the age of the youngest child and the length of the take‐up is related to the number of children, both were included as additional control variables. The age of the youngest child (time‐varying) was measured as: less than 1 year , between 1–2 years (when the couple is eligible for CFC), and 3+ years (not eligible), and the number of children (time‐varying) was measured as 1, 2, 3, and 4 or more children. All time‐varying control variables were lagged by 1 year. Table Our analysis followed three stages. First, we fit logistic regression models to estimate the effects of CFC use on the union dissolution risk using yearly discrete‐time event history data. Mothers are followed from when they were first eligible to receive CFC. We estimated three models: The first controlled for duration since first eligible for CFC, period, and duration of the union prior to the first birth. The second added controls of the couple's sociodemographic characteristics. The third model added the age of the youngest child and the number of children. Given how our CFC use variable is constructed, the analysis describes whether the union dissolution risk differs during and after CFC, as compared with mothers who had not used CFC by that year.Despite our rather extensive list of control variables, the estimates of the effects of CFC on union dissolution can be confounded by unobserved factors, such as unobserved human capital, values or family orientation, that affect both CFC use and the risk of union dissolution. Thus, second, we used fixed effects discrete‐time event history models for nonrepeated events Allison,  that conFixed effects models control for unobserved heterogeneity, but with the cost that they cannot be estimated with the same sample as the ordinary event history models. Specifically, the former are estimated using conditional logit models from cases with over‐time variation in the independent variable. In our case, couples who did not use CFC during the follow‐up period (9%), or used it during all the observed years (20%) were excluded from this analysis. Couples thus vary only in how many years—not whether—they used CFC. To better compare the results between fixed effects and ordinary event history models—in order to assess bias from unobserved heterogeneity—we estimated models on the same sample as in the fixed effects analysis using ordinary event history models with logistic regression, with the same control variables as above. We compared the results statistically using the Hausman test; as an additional check, re‐ran the analysis by estimating a random effects model on the same sample and reached the same conclusions. Fixed effects models controlled for confounding from time‐constant factors, but as is the case with all fixed effects models, the method does not control for time‐varying unobserved variables or the effects of anticipation of separation on labor supply  income and economic independence, but replicated the findings using her education likewise. These interaction effects were included in both the regular and the fixed effects event history models.Nine percent of mothers in our sample did not receive CFC following the birth of any of their children. This is consistent with previous findings that a large majority of Finnish mothers use the benefit for at least some time after the parental leave period. In addition to mothers that never received CFC during the follow‐up period, the reference category in the time‐varying “CFC use” variable , the estimate for CFC use is reduced and the estimates for the years since CFC use are close to 1 and no longer statistically significant. By construction of the policy, CFC use overlaps with the time when children are young, which is also the time when separation rates are low in any case. Although this confounds part of the CFC use effect, Model 3 shows that couples still have a 15% lower separation risk while they are using CFC compared to couples who have not used it previously. The “catch‐up” effect after CFC use (found in Models 1 and 2) is completely confounded; the years after CFC use overlap with the time when the youngest child is beyond the toddler‐age and separation rates are higher. Overall, the results from Model 3 do not support a postponement effect but point to a small temporary reduction in union dissolution risks during CFC use, which then returns back to the baseline level after the use period.Additional analyses .The upper panel in Table The middle panel shows the estimates from regular discrete‐time event history models on the same data as used to estimate the fixed effects models. These estimates are more directly comparable to the fixed effects ones than the estimates presented in Table The results presented thus far indicate a temporary effect of CFC take‐up whereby separation risk is reduced while using CFC, but also point toward a postponement of separation until after CFC use. Results also indicate that less advantaged mothers are more likely to use CFC and use it for longer  and the mother's income prior to first birth were estimated for both the event history models and the fixed effects models. The income categories were defined through percentiles, representing a 25, 50 and 90 percent cut off. The highest category of above 28,000 euro is the smallest group, but still spans over 6,000 couples and 13 percent of the couple‐years at risk. Figure df = 15; p = .0031). The interaction results indicate that the temporary reduction in separation risk while CFC is received is limited to higher earning mothers, and that there are no differences by income in the effect in the years after CFC use  after the latest CFC receipt. One year after CFC use a slight increase in separation risk can be seen for all income groups but the highest. Two to four years after the latest CFC receipt, the separation risk across all income categories increased slightly. This increase is not equal for all income groups; instead we find the starkest effect for the highest income group. Five to seven years after CFC use, the strongest effect can again be seen among higher earning mothers. Postponement of separation until 5–7 years after the leave is, therefore, more marked for couples where her previous income was high.Figure The relationship between women's employment and separation has been the focus of many studies. In a gender‐egalitarian context such as Finland, mothers' employment rates are close to those of fathers', and policies that negatively affect maternal employment, such as the CFC benefit, can contradict the more general policy aims of gender equality. The CFC policy indirectly promotes at least a temporary gendered division of labor within couples and leads to longer periods outside the labor market among young mothers that can result in loss of economic and human capital. This study used Finnish register data from 1987–2009 to analyze the effects of CFC use on union dissolution.We estimated discrete‐time event history models, with and without fixed effects that control for unobserved time‐constant factors. The results from the regular event history models without fixed effects show that, net of the effects of all control variables, separation rates are lower while CFC is received, but there is no effect in the years following the take‐up compared to couples who have not used CFC. This suggests that any effect of CFC use is temporary and does not alter couples' separation rates in the long run. Hardoy and Schøne  estimateThese results could, however, be biased due to direct and indirect selection into CFC use. To control for time‐constant unobserved factors, we estimated fixed effects models for nonrepeated events. The estimates from these models generalize to a different population—excluding couples that either never used CFC, or used it during all observed years—and use within‐couple rather than between‐couple variation like the estimates from ordinary discrete‐time event history models. The results from the fixed effects models suggest that CFC use has a stronger negative effect on the separation risk than in the previous discrete‐time models. However, this union stabilizing effect is only temporary, and is followed by a postponement or catch‐up effect in which separation risk increased after its use. A comparison between the fixed‐ and ordinary discrete‐time event history models furthermore suggests a strong selection into (longer episodes of) CFC use, in which couples with a higher unobserved separation propensity use CFC more than those with a lower separation propensity. A likely explanation for our result is unmeasured socioeconomic characteristics: Finnish couples with a weak socioeconomic profile are more likely to use CFC, and are also more likely to subsequently separate  for the research consortium Tackling Inequality in Time of Austerity, the Academy of Finland , the Swedish Research Council through the Linnaeus Center for Social Policy and Family Dynamics in Europe (grant 349‐2007‐8701), the Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM): Stockholm University SIMSAM Node for Demographic Research (grant 340‐2013‐5164) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program . We would like to thank Sunnee Billingsley, Ann‐Zofie Duvander, Rense Nieuwenhuis, Peter Fallesen and Lynn Prince Cooke for valuable comments, and Josh Blamire for proofreading.Appendix S1: Supporting InformationClick here for additional data file.


To the editor:We read with interest the proposal for segmented peer review by Dr Dinakaran et al. Librarians are, of course, well positioned to evaluate complicated search strategies and the methodologies of evidence syntheses. In 2018, we surveyed medical librarians to understand their experiences as peer reviewers of systematic reviews and other evidence synthesis papers and learned that some librarians decline to review papers because they do not feel competent to evaluate the whole papers. One quote that we included in the article: “I was asked to review the entire systematic review, which I did not feel competent to do. Had they asked for the search methods/search strategy only, I would have been happy to do so.” We also offer the parallel example of statisticians, who are frequently asked to peer review sections of papers that involved complex statistics, without needing to comment on the entire manuscript. [2]Journal editors seeking peer reviewers with expertise in evaluating systematic searches are invited to use the Librarian Peer Reviewer Database. Segmented peer review as proposed by Dinakaran et al could reduce the burden on individual reviewers while also welcoming into the peer review ecosystem reviewers whose deep (if narrow) expertise is important in ensuring the high quality of accepted manuscripts.Kate Nyhan: Writing – original draft, Writing – review & editing. Holly K. Grossetta Nardini: Writing – original draft, Writing – review & editing.