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Summary Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding Humanigen.

Binocular rivalry occurs when incompatible images are presented simultaneously but separately to each eye. Perceptual dominance reverses over time such that one image temporarily dominates perception, while the other image is suppressed. Prior research has shown that briefly-presented probes modulate perception such that probes presented to the suppressed eye tend to produce shorter percept durations relative to when probes are presented to the dominant eye. This pattern suggests that probes strengthen the competitive strength of the image over which they appear. However, it remains unclear whether probe-modulated effects on binocular rivalry are equivalent across the visual field, in particular as a function of whether probes appear within the region of interocular conflict (i.e on-object) or outside the region of interocular conflict (i.e. off-object). We tested this by manipulating whether probes appeared on-object or off-object. We replicate prior work showing that suppressed-eye probes produce shorter percept durations relative to dominant-eye probes. Critically, however, we show that percept duration also varies as a function of whether probes appear on vs. off the rivalry objects; that is, differences in percept duration between suppressed-eye and dominant-eye probes were much larger for on-object than off-object probes. Importantly, however, the difference between suppressed-eye and dominant-eye probes was still significant for off-object probes. Together these results suggest dynamic mechanisms at work in probe-mediated rivalry, such that on-object probe effects are larger relative to smaller, yet reliable off-object effects.

Skin-interfaced medical devices are critically important for diagnosing disease, monitoring physiological health and establishing control interfaces with prosthetics, computer systems and wearable robotic devices. Skin-like epidermal electronic technologies can support these use cases in soft and ultrathin materials that conformally interface with the skin in a manner that is mechanically and thermally imperceptible. Nevertheless, schemes so far have limited the overall sizes of these devices to less than a few square centimetres. Here, we present materials, device structures, handling and mounting methods, and manufacturing approaches that enable epidermal electronic interfaces that are orders of magnitude larger than previously realized. As a proof-of-concept, we demonstrate devices for electrophysiological recordings that enable coverage of the full scalp and the full circumference of the forearm. Filamentary conductive architectures in open-network designs minimize radio frequency-induced eddy currents, forming the basis for structural and functional compatibility with magnetic resonance imaging. We demonstrate the use of the large-area interfaces for the multifunctional control of a transhumeral prosthesis by patients who have undergone targeted muscle-reinnervation surgery, in long-term electroencephalography, and in simultaneous electroencephalography and structural and functional magnetic resonance imaging.

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) to characterize the spatio-temporal dynamics of attention and 2) to examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations.

Experimentalists studying multisensory integration compare neural responses to multisensory stimuli with responses to the component modalities presented in isolation. This procedure is problematic for multisensory speech perception since audiovisual speech and auditory-only speech are easily intelligible but visual-only speech is not. To overcome this confound, we developed intracranial encephalography (iEEG) deconvolution. Individual stimuli always contained both auditory and visual speech but jittering the onset asynchrony between modalities allowed for the time course of the unisensory responses and the interaction between them to be independently estimated. We applied this procedure to electrodes implanted in human epilepsy patients (both male and female) over the posterior superior temporal gyrus (pSTG), a brain area known to be important for speech perception. iEEG deconvolution revealed sustained, positive responses to visual-only speech and larger, phasic responses to auditory-only speech. Confirming results from scalp EEG, responses to audiovisual speech were weaker than responses to auditory- only speech, demonstrating a subadditive multisensory neural computation. Leveraging the spatial resolution of iEEG, we extended these results to show that subadditivity is most pronounced in more posterior aspects of the pSTG. Across electrodes, subadditivity correlated with visual responsiveness, supporting a model in visual speech enhances the efficiency of auditory speech processing in pSTG. The ability to separate neural processes may make iEEG deconvolution useful for studying a variety of complex cognitive and perceptual tasks.Significance statementUnderstanding speech is one of the most important human abilities. Speech perception uses information from both the auditory and visual modalities. It has been difficult to study neural responses to visual speech because visual-only speech is difficult or impossible to comprehend, unlike auditory-only and audiovisual speech. We used intracranial encephalography (iEEG) deconvolution to overcome this obstacle. We found that visual speech evokes a positive response in the human posterior superior temporal gyrus, enhancing the efficiency of auditory speech processing.

Research on the neural correlates of consciousness (NCC) has implicated an assortment of brain regions, ERP components, and network properties associated with visual awareness. Recently, the P3b ERP component has emerged as a leading NCC candidate. However, typical P3b paradigms depend on the detection of some stimulus change, making it difficult to separate brain processes elicited by the stimulus itself from those associated with updates or changes in visual awareness. Here we used binocular rivalry to ask whether the P3b is associated with changes in awareness even in the absence of changes in the object of awareness. We recorded ERPs during a probe-mediated binocular rivalry paradigm in which brief probes were presented over the image in either the suppressed or dominant eye to determine whether the elicited P3b activity is probe or reversal related. We found that the timing of P3b (but not its amplitude) was closely related to the timing of the report of a perceptual change rather than to the onset of the probe. This is consistent with the proposal that P3b indexes updates in conscious awareness, rather than being related to stimulus processing per se. Conversely, the probe-related P1 amplitude (but not its latency) was associated with reversal latency, suggesting that the degree to which the probe is processed increases the likelihood of a fast perceptual reversal. Finally, the response-locked P3b amplitude (but not its latency) was associated with the duration of an intermediate stage between reversals in which parts of both percepts coexist (piecemeal period). Together, the data suggest that the P3b reflects an update in consciousness and that the intensity of that process (as indexed by P3b amplitude) predicts how immediate that update is.

Cryptococcus neoformans meningitis occurs in 30%–50% of human immunodeficiency virus (HIV)–infected individuals in sub-Saharan Africa and the developing world [1–3] and accounts for 13%–44% of all HIV-associated deaths in the developing world [4]. A recent analysis estimated that, each year, there are >900,000 cases of and ~600,000 deaths due to C. neoformans meningitis globally, with most cases occurring in sub-Saharan Africa [5]. Although the incidence of C. neoformans meningitis has decreased dramatically in the United States and parts of the world where antiretroviral therapy is available [1], this disease has emerged as an important complication of solid organ transplantation [6, 7] and immune reconstitution syndrome [8]. HIV-associated cryptococcosis almost always occurs when an individual’s CD4+ T cell level is significantly