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Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Abstract Footshock self-experience enhances rodents’ reactions to the distress of others. Here, we tested one potential mechanism supporting this phenomenon, namely that animals auto-condition to their own pain squeaks during shock pre-exposure. In Experiment 1, shock pre-exposure increased freezing and 22 kHz distress vocalizations while animals listened to the audible pain-squeaks of others. In Experiment 2 and 3, to test the auto-conditioning theory, we weakened the noxious pre-exposure stimulus not to trigger pain squeaks, and compared pre-exposure protocols in which we paired it with squeak playback against unpaired control conditions. Although all animals later showed fear responses to squeak playbacks, these were weaker than following typical pre-exposure (Experiment 1) and not stronger following paired than unpaired pre-exposure. Experiment 1 thus demonstrates the relevance of audible pain squeaks in the transmission of distress but Experiment 2 and 3 highlight the difficulty to test auto-conditioning: stimuli weak enough to decouple pain experience from hearing self-emitted squeaks are too weak to trigger the experience-dependent increase in fear transmission that we aimed to study. Although our results do not contradict the auto-conditioning hypothesis, they fail to disentangle it from sensitization effects. Future studies could temporarily deafen animals during pre-exposure to further test this hypothesis.

Abstract Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca2+ imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca2+ activity became increasingly related to reward during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, “reward off sustained”, “reward off transient”, “reward on sustained” and “reward on transient”, and these responses showed reorganization after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent reward- related activity during learning. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Abstract Materials tuned to a quantum critical point display universal scaling properties as a function of temperature T and frequency ω. A long-standing puzzle regarding cuprate superconductors has been the observed power-law dependence of optical conductivity with an exponent smaller than one, in contrast to T-linear dependence of the resistivity and ω-linear dependence of the optical scattering rate. Here, we present and analyze resistivity and optical conductivity of La2−x Sr x CuO4 with x = 0.24. We demonstrate ℏ ω/k B T scaling of the optical data over a wide range of frequency and temperature, T-linear resistivity, and optical effective mass proportional to $$\sim \ln T$$ ~ ln T corroborating previous specific heat experiments. We show that a T, ω-linear scaling Ansatz for the inelastic scattering rate leads to a unified theoretical description of the experimental data, including the power-law of the optical conductivity. This theoretical framework provides new opportunities for describing the unique properties of quantum critical matter.

Abstract Vonoprazan is metabolized extensively through CYP3A and is an in vitro time‐dependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug–drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically‐based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug‐ and system‐specific parameters, and clinical data and observations from a [14C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time‐dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co‐administration with moderate and strong CYP3A inducers should be avoided.

Abstract We build new material descriptors to predict the band gap and the work function of 2D materials by tree-based machine-learning models. The descriptor’s construction is based on vectorizing property matrices and on empirical property function, leading to mixing features that require low-resource computations. Combined with database-based features, the mixing features significantly improve the training and prediction of the models. We find R $$^{2}$$ 2 greater than 0.9 and mean absolute errors (MAE) smaller than 0.23 eV both for the training and prediction. The highest R $$^{2}$$ 2 of 0.95, 0.98 and the smallest MAE of 0.16 eV and 0.10 eV were obtained by using extreme gradient boosting for the bandgap and work-function predictions, respectively. These metrics were greatly improved as compared to those of database features-based predictions. We also find that the hybrid features slightly reduce the overfitting despite a small scale of the dataset. The relevance of the descriptor-based method was assessed by predicting and comparing the electronic properties of several 2D materials belonging to new classes (oxides, nitrides, carbides) with those of conventional computations. Our work provides a guideline to efficiently engineer descriptors by using vectorized property matrices and hybrid features for predicting 2D materials properties via ensemble models.

Carbon-based catalyst can effectively crack model waste plastic based on polyolefins under contactless induction heating and yield gaseous and liquid hydrocarbons fractions at mild reaction temperatures. High catalytic performances are reached thanks to the stable catalyst bed temperature arising from the high heating rate of the induction setup. By comparison to indirect Joule heating which required much higher temperatures, contactless direct induction heating allows a compensation of the internal temperature loss during such highly endothermic process through direct heat targeting. The single carbon-based catalyst combined a high and stable activity with an extremely high stability as a function of cycling tests with pure or mixed polymers. By comparison to the acid or metal based catalysts used in plastic cracking, such low cost carbon catalyst avoids deactivation within cycling tests and therefore provides an efficient and cost-effective route for waste plastic recycling and also as chemical storage means for renewable energy.

Summary: The action observation network (AON) has been extensively studied using short, isolated motor acts. How activity in the network is altered when these isolated acts are embedded in meaningful sequences of actions remains poorly understood. Here we utilized intracranial electrocorticography to characterize how the exchange of information across key nodes of the AON—the precentral, supramarginal, and visual cortices—is affected by such embedding and the resulting predictability. We found more top-down beta oscillation from precentral to supramarginal contacts during the observation of predictable actions in meaningful sequences compared to the same actions in randomized, and hence less predictable, order. In addition, we find that expectations enabled by the embedding lead to a suppression of bottom-up visual responses in the high-gamma range in visual areas. These results, in line with predictive coding, inform how nodes of the AON integrate information to process the actions of others.

Repetitive transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical settings to modulate human cortical activity. The effects of TMS on neural activity depend on the excitability of specific neural populations at the time of stimulation. Accordingly, the brain state at the time of stimulation may influence the persistent effects of repetitive TMS on distal brain activity and associated behaviors. We applied intermittent theta burst stimulation (iTBS) to a region in the posterior parietal cortex (PPC) associated with grasp control to evaluate the interaction between stimulation and brain state. Across two experiments, we demonstrate the immediate responses of motor cortex activity and motor performance to state-dependent parietal stimulation. We randomly assigned 72 healthy adult participants to one of three TMS intervention groups, followed by electrophysiological measures with TMS and behavioral measures. Participants in the first group received iTBS to PPC while performing a grasping task concurrently. Participants in the second group received iTBS to PPC while in a task-free, resting state. A third group of participants received iTBS to a parietal region outside the cortical grasping network while performing a grasping task concurrently. We compared changes in motor cortical excitability and motor performance in the three stimulation groups within an hour of each intervention. We found that parietal stimulation during a behavioral manipulation that activates the cortical grasping network increased downstream motor cortical excitability and improved motor performance relative to stimulation during rest. We conclude that constraining the brain state with a behavioral task during brain stimulation has the potential to optimize plasticity induction in cortical circuit mechanisms that mediate movement processes.

In humans, ankyloglossia and cleft palate are common congenital craniofacial anomalies, and these are regulated by a complex gene regulatory network. Understanding the genetic underpinnings of ankyloglossia and cleft palate will be an important step toward rational treatment of these complex anomalies. We inactivated the Sry (sex-determining region Y)-box 2 (Sox2) gene in the developing oral epithelium, including the periderm, a transient structure that prevents abnormal oral adhesions during development. This resulted in ankyloglossia and cleft palate with 100% penetrance in embryos examined after embryonic day 14.5. In Sox2 conditional knockout embryos, the oral epithelium failed to differentiate, as demonstrated by the lack of keratin 6, a marker of the periderm. Further examination revealed that the adhesion of the tongue and mandible expressed the epithelial markers E-Cad and P63. The expanded epithelia are Sox9-, Pitx2-, and Tbx1-positive cells, which are markers of the dental epithelium; thus, the dental epithelium contributes to the development of oral adhesions. Furthermore, we found that Sox2 is required for palatal shelf extension, as well as for the formation of palatal rugae, which are signaling centers that regulate palatogenesis. In conclusion, the deletion of Sox2 in oral epithelium disrupts palatal shelf extension, palatal rugae formation, tooth development, and periderm formation. The periderm is required to inhibit oral adhesions and ankyloglossia, which is regulated by Sox2. In addition, oral adhesions occur through an expanded dental epithelial layer that inhibits epithelial invagination and incisor development. This process may contribute to dental anomalies due to ankyloglossia.

Geophysical and geological data from the North Mozambique Channel acquired during the 2020–2021 SISMAORE oceanographic cruise reveal a corridor of recent volcanic and tectonic features 200 km wide and 600 km long within and north of Comoros Archipelago. Here we identify and describe two major submarine tectono-volcanic fields: the N’Droundé province oriented N160°E north of Grande-Comore Island, and the Mwezi province oriented N130°E north of Anjouan and Mayotte Islands. The presence of popping basaltic rocks sampled in the Mwezi province suggests post-Pleistocene volcanic activity. The geometry and distribution of recent structures observed on the seafloor are consistent with a current regional dextral transtensional context. Their orientations change progressively from west to east (${\sim }$N160°E, ${\sim }$N130°E, ${\sim }$EW). The volcanism in the western part appears to be influenced by the pre-existing structural fabric of the Mesozoic crust. The 200 km-wide and 600 km-long tectono-volcanic corridor underlines the incipient Somalia–Lwandle dextral lithospheric plate boundary between the East-African Rift System and Madagascar.

Teleseismic receiver-functions and Rayleigh-wave dispersion curves are jointly inverted for quantifying $S$-wave velocity profiles beneath the active volcanic zone off Mayotte. We show that the lithosphere in the east-northeast quadrant is composed of four main layers, interpreted as the volcanic edifice, the crust with underplating, the lithospheric mantle, and the asthenosphere, the latter two presenting a main low-velocity zone. The depths of the old (10–11 km) and new Moho (28–31 km) coincide with the two magma reservoirs evidenced by recent seismological and petrological methods. We propose that the main magma reservoir composed of mush with an increasing amount of liquid extends down to 54 km depth. This magma storage develops from a rheological contrast between the ductile lower and brittle upper lithospheric mantle and accounts for most of the volcanic eruption-related seismicity. Finally, the abnormally small thickness of the lithospheric mantle (33 km) is likely a result of a thermal thinning since the onset of Cenozoic magmatism.

Corneal blindness is the fourth leading cause of blindness worldwide. Since corneal epithelium is constantly renewed, non-integrative gene transfer cannot be used to treat corneal diseases. In many of these diseases, the tear film is defective. Tears are a complex biological fluid secreted by the lacrimal apparatus. Their composition is modulated according to the context. After a corneal wound, the lacrimal gland secretes reflex tears, which contain growth factors supporting the wound healing process. In various pathological contexts, the tear composition can support neither corneal homeostasis nor wound healing. Here, we propose to use the lacrimal gland as bioreactor to produce and secrete specific factors supporting corneal physiology. In this study, we use an AAV2/9-mediated gene transfer to supplement the tear film. First, we demonstrate that a single injection of AAV2/9 is sufficient to transduce all epithelial cell types of the lacrimal gland efficiently and widely. Second, we detect no adverse effect after AAV2/9-mediated nerve growth factor expression in the lacrimal gland. Only a transitory increase in tear flow is measured. Remarkably, AAV2/9 induces an important and long-lasting secretion of this growth factor in the tear film. Altogether, our findings provide a new clinically applicable approach to tackle corneal blindness.

PurposeTo identify risk factors for sickle cell maculopathy due to hematological parameters (especially anemia and hemolysis) or cerebral vasculopathy.MethodsThis retrospective study was conducted at a Referral Center. The follow-up included optical coherent tomography/optical coherent tomography angiography, neuro-radiological imaging, and a hematological assessment (hemoglobin, hemoglobin S level, reticulocytes, mean corpuscular volume, bilirubin, and lactate dehydrogenase).ResultsHundred and thirty-two sickle cell patients were included. Maculopathy was observed in 127 eyes of SS patients and 10 eyes of SC patients (p < 0.001), unrelated to peripheral retinopathy. Cerebral vasculopathy was more frequent in SS patients (p < 0.001) and was also associated with the presence of maculopathy (p = 0.049), and it was related to peripheral retinopathy (p < 0.001). All biological parameters significantly differed according to the genotype (p < 0.001) but not according to the presence of cerebral vasculopathy or maculopathy. In the multivariate analysis, reticulocytes and bilirubin were associated with the presence of cerebral vasculopathy and maculopathy.ConclusionThe data obtained were consistent with the role of anemia or hemolysis markers in cerebral vasculopathy and macular involvement. As a trend of hemolysis appears to be a risk factor for these complications, this validates the use of preventive plasmapheresis in these patients.

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

The aim of this article is to investigate the parameter sensitivity of the (Non-Linear) Unsteady Vortex Lattice Method-Vortex Particle Method [(NL-)UVLM-VPM] with Particle Strength Exchange-Large Eddy Simulations (PSE-LES) method on a lower Reynolds number rotor. The previous work detailed the method, but introduced parameters whose influence were not investigated. Most importantly, the Vreman model coefficient was chosen arbitrarily and was not suitable to ensure stability for this lower Reynolds number rotor simulation. In addition, the previous work presented a consistency study where geometry and time discretization were refined simultaneously. The present article starts with a comparative literature review of potential methods used to solve the aerodynamics of an isolated hovering rotor. This review highlights the differences in modeling, discretizations, sensitivity analysis, validation cases, and the results chosen by the different studies. Then, a transparent and thorough parametric study of the method is presented alongside discussions of the observed results and their physical interpretation regarding the flow. The sensitivity analysis is performed for the three free parameters of UVLM, namely Vatistas core size, the geometry and the temporal discretizations, and then for the three additional parameters introduced by UVLM-VPM, which are the Vreman model coefficient, the particle spacing, and the conversion time. The effect of different databases in the non-linear coupling is also shown. The method is shown to be consistent with both geometry and temporal refinements. It is also consistent with the expected behavior of the different parameters change, including the numerical stability that depends on the strength of the LES diffusion controlled by the Vreman model coefficient. The effect of discretization refinement presented here not only shows the integrated coefficients where different errors can cancel each other, but also looks at their convergence and where relevant, the distributed loads and tip singularity position. Finally, the aerodynamics results of the method are compared for different databases and with higher fidelity Unsteady Reynolds Averaged Navier–Stokes (URANS) 3D results on a lower Reynolds number rotor.

Abstract Background Individual Placement and Support (IPS) is an evidence-based, effective approach to help people with severe mental illness (SMI) obtain and maintain competitive employment. The aim of the present study was to examine employment outcomes and associations with an organizational and a financial factor in people with SMI who participated in Individual Placement and Support using a multifaceted implementation strategy (IPS + MIS). The goal of this strategy was to improve IPS implementation by enhancing collaboration among mental health care and vocational rehabilitation stakeholders, and realizing secured IPS funding. Methods An observational cohort study including 103 participants was conducted, with a 30-month follow-up. Descriptive analyses were used to examine employment outcomes. Multivariable logistic and linear regression analyses were performed to study associations with an organizational and a financial factor: the level of experience of mental health agencies with providing IPS + MIS and the type of IPS funding (i.e. municipality funding (reference group) and the Dutch Social Security Institute: the Institute for Employee Benefits Schemes (UWV) funding). Results Forty-six percent of the participants were competitively employed at any time during the 30-month follow-up; the median number of days until competitive job obtainment and in competitive jobs was 201 and 265, respectively. The majority of all jobs obtained (81%) were categorized as ‘elementary occupations’, ‘clerical support workers’, and ‘service and sales workers’. A higher level of experience of the mental health agencies with providing IPS + MIS was found to be positively associated with job obtainment (OR = 3.83, 95% CI 1.42–10.30, p = 0.01) and the number of days worked in competitive jobs (B = 1.21, 95% CI 0.36–2.07, p = 0.01). UWV funding was found to be negatively associated with job obtainment (OR = 0.30, 95% CI 0.11–0.77, p = 0.01). No association was found for the type of IPS funding and the number of days worked in competitive jobs (B = -0.73, 95% CI -1.48–0.02, p = 0.06). Conclusions This study shows that almost half of the people who participate in IPS + MIS obtain a competitive job within 30 months. The results further suggest that both the level of experience of mental health agencies with providing IPS + MIS, and funding may play a role in employment outcomes.

Multimodal imitation of actions, gestures and vocal production is a hallmark of the evolution of human communication, as both, vocal learning and visual-gestural imitation, were crucial factors that facilitated the evolution of speech and singing. Comparative evidence has revealed that humans are an odd case in this respect, as the case for multimodal imitation is barely documented in non-human animals. While there is evidence of vocal learning in birds and in mammals like bats, elephants and marine mammals, evidence in both domains, vocal and gestural, exists for two Psittacine birds (budgerigars and grey parrots) and cetaceans only. Moreover, it draws attention to the apparent absence of vocal imitation (with just a few cases reported for vocal fold control in an orangutan and a gorilla and a prolonged development of vocal plasticity in marmosets) and even for imitation of intransitive actions (not object related) in monkeys and apes in the wild. Even after training, the evidence for productive or “true imitation” (copy of a novel behavior, i.e., not pre-existent in the observer’s behavioral repertoire) in both domains is scarce. Here we review the evidence of multimodal imitation in cetaceans, one of the few living mammalian species that have been reported to display multimodal imitative learning besides humans, and their role in sociality, communication and group cultures. We propose that cetacean multimodal imitation was acquired in parallel with the evolution and development of behavioral synchrony and multimodal organization of sensorimotor information, supporting volitional motor control of their vocal system and audio-echoic-visual voices, body posture and movement integration.