Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study.

BACKGROUND: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment. METHODS: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry. FINDINGS: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes. INTERPRETATION: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.

Spatial perception in stereoscopic augmented reality based on multifocus sensing.

In many areas ranging from medical imaging to visual entertainment, 3D information acquisition and display is a key task. In this regard, in multifocus computational imaging, stacks of images of a certain 3D scene are acquired under different focus configurations and are later combined by means of post-capture algorithms based on image formation model in order to synthesize images with novel viewpoints of the scene. Stereoscopic augmented reality devices, through which is possible to simultaneously visualize the three dimensional real world along with overlaid digital stereoscopic image pair, could benefit from the binocular content allowed by multifocus computational imaging. Spatial perception of the displayed stereo pairs can be controlled by synthesizing the desired point of view of each image of the stereo-pair along with their parallax setting. The proposed method has the potential to alleviate the accommodation-convergence conflict and make augmented reality stereoscopic devices less vulnerable to visual fatigue.

Real-time phase retrieval in division of aperture microscopy with the transport of intensity equation.

The transport of intensity equation (TIE) allows to recover the phase of a microscopy sample from differently focused intensity measures along the axial direction of its optical field. In the present work, we propose a cost-effective technique for snapshot phase retrieval with TIE. The optics of a commercially available camera is replaced with a doublet system consisting of a microscope objective and a lenslet array with an extra lens mask attached to it. The system allows to obtain, in real-time and with no mechanical shift of either the sample or the sensor, the in-focus as well as a defocused image of the sample. From these two sub-aperture images, the intensity derivative term in TIE can then be approximated after image rectification. Phase is then retrieved for static as well as dynamic samples over the common view area. Validation experiments are presented.

Generalized Hough transform for 3D object recognition and visualization in integral imaging.

Object recognition is an automated image processing application of great interest in areas ranging from defect inspection to robot vision. In this regard, the generalized Hough transform is a well-established technique for the recognition of geometrical features even when they are partially occluded or corrupted by noise. To extend the original algorithm-aimed at detecting 2D geometrical features out of single images-we propose the robust integral generalized Hough transform, which corresponds to transformation under the generalized Hough transform of an elemental image array obtained from a 3D scene under integral imaging capture. The proposed algorithm constitutes a robust approach to pattern recognition in 3D scenes that takes into account information obtained not only from the individual processing of each image of the array but also from the spatial restrictions arising from perspective shifts between images. The problem of global detection of a 3D object of given size, position, and orientation is then exchanged under the robust integral generalized Hough transform for a more easily solved maximum detection in an accumulation (Hough) space dual to the elemental image array of the scene. Detected objects can then be visualized following refocusing schemes of integral imaging. Validation experiments for the detection and visualization of partially occluded 3D objects are presented. To the best of our knowledge, this is the first implementation of the generalized Hough transform for 3D object detection in integral imaging.

Can Intubation Be Improved with Endotracheal Tubes Marked with a Color Scale? Randomized Controlled Study.

OBJECTIVE: This study aimed to assess if a color scale in the endotracheal tube (ETT) can help operators to correctly select the size and depth of placement of the ETT and decrease the time required to complete the procedure and compared with the usual numeric ETT scale in a mannequin model. STUDY DESIGN: The study was conducted in eight centers. Each size of the ETT was identified with a different color. The experimental ETTs had two different colored areas, one for the mouthpiece and another to identify where the ETT should be taped above the lip (an area of 1 cm. The operators were trained as part of the protocol using an instructional video. Four clinical scenarios requiring endotracheal intubation were designed and randomly assigned. Each operator had to select the size and depth of ETT based on the birth weight (BW), and then had to perform four intubations. RESULTS: A total of 108 operators performed 432 intubations. No differences were found in the correct placement and selection of the ETT. Median time (in seconds) required for intubation using numeric versus experimental tube was: for ETT Ø NRP (Neonatal Resuscitation Program) 2.5, 11.5 versus 8 (p < 0.001), ETT Ø 3, 12 versus 10 (p < 0.001), ETT Ø 3.5, 15.5 versus12 (p = 0.003), ETT Ø 4, 12 versus11 (p = 0.019). CONCLUSION: No significant difference was observed in the selection and correct placement of the ETT. However, the intubation time was significantly shorter using the experimental ETT. This device could improve the effectiveness of intubation by reducing the time needed to properly place the ETT at mid trachea. KEY POINTS: · It is an innovative intervention to try to solve a great inconvenience of daily practice.. · The study also raises the difficulty in maintaining the ability of endotracheal intubation.. · It proposes a scale that ensures the correct location with a safe fixation zone..

Snapshot polarimetric imaging in multi-view microscopy.

Polarimetric imaging allows for the vector nature of optical information across a scene to be obtained, with recent applications ranging from remote sensing to microscopy. In polarimetric microscopy in particular, different polarization states are conventionally achieved under time-division multiplexing strategies and are mainly subject to static phenomena. In the present work, we propose a cost-effective technique for polarization sensing with the possibility of real-time imaging microscopy. By modifying a commercial camera and replacing the conventional lens with an optical system that integrates a microscope objective and a lenslet array with a polarization mask, linear Stokes parameters can be obtained in a snapshot. The proposed scheme is robust against misalignment and suitable for handling video sequences of microscopic samples. To the best of our knowledge, this is the first report on combining multi-view sensing and polarization imaging for applications to microscopy.

Withdrawn: Supramolecular Evolution of Protein Organization.

Ahead of Print article withheld by publisher: It has come to the publisher's attention that some key concepts reviewed in the manuscript entitled "Supramolecular Evolution of Protein Organization" by Ariel Fernández (scheduled to appear in Volume 47 of the Annual Review of Genetics) derive from at least one article in the primary research literature currently under dispute due to unsettled anomalies in the data and/or interpretation. Annual Reviews, with concurrence of the review's author, has decided to withhold final publication pending satisfactory resolution.

Driving the catalytic activity of a transmembrane thermosensor kinase.

DesK is a Bacillus thermosensor kinase that is inactive at high temperatures but turns activated when the temperature drops below 25 °C. Surprisingly, the catalytic domain (DesKC) lacking the transmembrane region is more active at higher temperature, showing an inverted regulation regarding DesK. How does the transmembrane region control the catalytic domain, repressing activity at high temperatures, but allowing activation at lower temperatures? By designing a set of temperature minimized sensors that share the same catalytic cytoplasmic domain but differ in number and position of hydrogen-bond (H-bond) forming residues along the transmembrane helix, we are able to tune, invert or disconnect activity from the input signal. By favoring differential H-bond networks, the activation peak could be moved towards lower or higher temperatures. This principle may be involved in regulation of other sensors as environmental physicochemical changes or mutations that modify the transmembrane H-bond pattern can tilt the equilibrium favoring alternative conformations.

Artificial Intelligence Teaches Drugs to Target Proteins by Tackling the Induced Folding Problem.

We explore the possibility of a deep learning (DL) platform that steers drug design to target proteins by inducing binding-competent conformations. We deal with the fact that target proteins are usually not fixed targets but structurally adapt to the ligand in ways that need to be predicted to enable pharmaceutical discovery. In contrast with protein folding predictors, the proposed DL system integrates signals for structural disorder to predict conformations in floppy regions of the target protein that rely on associations with the purposely designed drug to maintain their structural integrity. This is tantamount to solve the drug-induced folding problem within an AI-empowered drug discovery platform. Preliminary testing of the proposed DL platform reveals that it is possible to infer the induced folding ensemble from which a therapeutically targetable conformation gets selected by DL-instructed drug design.

Artificial Intelligence Steering Molecular Therapy in the Absence of Information on Target Structure and Regulation.

Protein associations are at the core of biological activity, and the drug-based disruption of dysfunctional associations poses a major challenge to targeted therapy. The problem becomes daunting when the structure and regulated modulation of the complex are unknown. To address the challenge, we leverage an artificial intelligence platform that learns from structural and epistructural data and infers regulation-susceptible regions that also generate interfacial tension between protein and water, thereby promoting protein associations. The input consists of sequence-derived 1D-features. The network is configured with evolutionarily coupled residues and taught to search for phosphorylation-modulated binding epitopes. The discovery platform is benchmarked against a PDB-derived testing set and validated against experimental data on a therapeutic disruptor designed according to the inferred epitope for a large deregulated complex known to be recruited in heart failure. Thus, dysfunctional "molecular brakes" of cardiac contractility get released through a therapeutic intervention guided by artificial intelligence.

Prevalence of Children With Complex Chronic Conditions in PICUs of Argentina: A Prospective Multicenter Study.

OBJECTIVES: To determine the prevalence of children with complex chronic conditions in PICUs in Argentina. To describe the demographic profile, clinical course and outcomes in PICU of children with complex chronic condition in comparison to previously healthy children. DESIGN: Prospective, observational multicenter study. SETTING: Nineteen PICUs located in Argentina belonging to public and private institutions. PATIENTS: All children admitted to the participating PICUs between March 1, 2015, and February 28, 2016. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We analyzed 3,483 PICU admissions. The prevalence of complex chronic condition was 48.06% (95% CI, 46.39-49.72). Cardiovascular complex chronic condition was predominant (22.24% [421/1,893]), followed by neuromuscular complex chronic condition (18.75% [355/1,893]) and malignant disease 17.7% (335/1,893). Technologic dependence was present in 22.22% of the patients (372 of 1,674). Predominant admission diagnosis was postoperative (36.6%) and respiratory disease (28.32%). Children with complex chronic condition had higher mortality than previously healthy patients (odds ratio, 2.74; 95% CI, 2.01-3.73). The risk of prolonged stay (≥ 26 d) was also higher (odds ratio, 1.44; 95% CI, 1.10-1.89). Rate utilization of the following devices was higher in patients with complex chronic condition: mechanical ventilation (odds ratio, 1.35; 95% CI, 1.12-1.63), central venous catheter (odds ratio, 1.24; 95% CI, 1.04-1.48), and arterial monitoring (odds ratio, 1.33; 95% CI, 1.09-1.63). CONCLUSIONS: We observed a high prevalence of patients with complex chronic condition in this sample of argentine PICUs. These patients presented higher mortality and resource use than previously healthy children. This information is valuable to understand the impact that patients with complex chronic condition have on PICU performance and enables proper planning of care.

Using a variant of coverslip hypoxia to visualize tumor cell alterations at increasing distances from an oxygen source.

Early stages in tumor development involve growth in confined spaces, where oxygen diffusion is limited and metabolic waste products accumulate. This hostile microenvironment imposes strong selective pressures on tumor cells, leading eventually to the survival and expansion of aggressive subclones that condition further tumor evolution. To model features of this microenvironment in vitro, a diffusional barrier can be introduced in the form of a coverslip placed on top of cells, a method termed coverslip hypoxia. Using a variant of this method, with larger volume between coverslip and cells and with oxygen diffusion occurring only through a small hole in the center of the coverslip, we have visualized alterations in LNCaP tumor cells as a function of their distance to the oxygen source at the center. We observed remarkable morphological changes in LNCaP cells as the distance from the center increases, with cells becoming highly spread, displaying dynamic membrane protrusions and occasionally adopting a migratory phenotype. Concomitantly, cells farther from the center displayed marked increases in the hypoxia marker hypoxyprobe, whereas extracellular pH decreased in the same direction. Cells with altered morphology displayed prominent increases in fibrillar actin, as well as swollen mitochondria with distorted cristae and accumulation of neutral lipid-containing intracellular vesicles. These results show that an in vitro microenvironment that models diffusional barriers encountered by tumors in situ can have profound effects on tumor cells. The coverslip hypoxia variant we describe can be used to characterize in vitro the response of tumor cells to environmental conditions that play crucial roles in early tumor development.

Protein structural defects enable pharmaceutical targeting while functionalizing the M2 proton channel.

The influenza M2 (22-46) proton channel is therapeutically targetable and a prototype for proton transport across membranes. Conduction initiation, requiring a hydronium formed with exceptionally high pKa, remains nebulous. We tackle the problem by focusing on the dynamic interplay between protein structure and solvent interface. We identify two packing defects in the protein subunits that predict exactly the low and high-affinity drug-binding sites. The latter defect frustrates water coordination, enhancing water basicity and stabilizing the nearby hydronium that forms upon proton penetration in the channel. Thus, the trigger of proton conduction is directly related to the high-affinity binding site. The findings, in quantitative agreement with affinity measurements, are consistent with the targetable functional nature of protein packing defects. These findings enable the design of proton-conducting biomimetic materials, where the epistructure may be engineered to tune the basicity of interfacial water.

Fully invariant generalized Hough transform by out-of-focus multiview sensing with pupil array.

Recognition of geometrical shapes in real-time and fully invariant (i.e., invariant under changes in position, scale, and orientation) is a demanding task in automated image analysis. In particular, the generalized Hough transform (GHT) is a well-known algorithm for the recognition of complex patterns out of edge binary images even with disconnected boundaries or corrupted by noise. In this work we present a space multiplexed optical implementation of the GHT which, by exploiting the redundancy derived from multiview sensing of a two-dimensional image and its out- of-focus capture with an adequate pupil array, allows us to obtain in a single shot the GHT of this image invariant to target shift, scale, and orientation. Experimental validation of the working principle is presented, along with an assessment of the robustness of the system against noise in the input.

Performance of the Pediatric Index of Mortality 3 Score in PICUs in Argentina: A Prospective, National Multicenter Study.

OBJECTIVE: To assess the performance of the Pediatric Index of Mortality 3 score in a population of children admitted to PICUs in Argentina. DESIGN: Prospective, national, multicenter study. SETTING: Forty-nine PICUs located in Argentina belonging to public and private institutions. PATIENTS: All children between 1 month and 16 years old admitted to the participating PICUs between May 15, 2016, and February 15, 2017. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A total of 6,602 patients were enrolled in the study. The observed mortality was 8% (531/6,602), whereas mortality predicted by Pediatric Index of Mortality 3 was 6.16% (407 deaths). The standardized mortality rate was 1.3 (95% CI, 1.20-1.42). The area under the receiver operating characteristic curve was 0.83 (95% CI, 0.82-0.85). The Hosmer-Lemeshow test showed that the difference between the mortality observed and the mortality predicted by Pediatric Index of Mortality 3 was statistically significant (χ, 135.63; p < 0.001). CONCLUSIONS: The Pediatric Index of Mortality 3 score adequately discriminated patients who died from those who survived in our population. However, the observed mortality was higher than predicted by the score. The use of an updated instrument such as Pediatric Index of Mortality 3 will allow an actual comparison between pediatric intensive care provided in the country and care provided internationally. This might also allow future planning of pediatric intensive care services in Argentina.

Non-adaptive origins of interactome complexity.

The boundaries between prokaryotes, unicellular eukaryotes and multicellular eukaryotes are accompanied by orders-of-magnitude reductions in effective population size, with concurrent amplifications of the effects of random genetic drift and mutation. The resultant decline in the efficiency of selection seems to be sufficient to influence a wide range of attributes at the genomic level in a non-adaptive manner. A key remaining question concerns the extent to which variation in the power of random genetic drift is capable of influencing phylogenetic diversity at the subcellular and cellular levels. Should this be the case, population size would have to be considered as a potential determinant of the mechanistic pathways underlying long-term phenotypic evolution. Here we demonstrate a phylogenetically broad inverse relation between the power of drift and the structural integrity of protein subunits. This leads to the hypothesis that the accumulation of mildly deleterious mutations in populations of small size induces secondary selection for protein-protein interactions that stabilize key gene functions. By this means, the complex protein architectures and interactions essential to the genesis of phenotypic diversity may initially emerge by non-adaptive mechanisms.

A lipid-mediated conformational switch modulates the thermosensing activity of DesK.

The thermosensor DesK is a multipass transmembrane histidine-kinase that allows the bacterium Bacillus subtilis to adjust the levels of unsaturated fatty acids required to optimize membrane lipid fluidity. The cytoplasmic catalytic domain of DesK behaves like a kinase at low temperature and like a phosphatase at high temperature. Temperature sensing involves a built-in instability caused by a group of hydrophilic residues located near the N terminus of the first transmembrane (TM) segment. These residues are buried in the lipid phase at low temperature and partially "buoy" to the aqueous phase at higher temperature with the thinning of the membrane, promoting the required conformational change. Nevertheless, the core question remains poorly understood: How is the information sensed by the transmembrane region converted into a rearrangement in the cytoplasmic catalytic domain to control DesK activity? Here, we identify a "linker region" (KSRKERERLEEK) that connects the TM sensor domain with the cytoplasmic catalytic domain involved in signal transmission. The linker adopts two conformational states in response to temperature-dependent membrane thickness changes: (i) random coiled and bound to the phospholipid head groups at the water-membrane interface, promoting the phosphatase state or (ii) unbound and forming a continuous helix spanning a region from the membrane to the cytoplasm, promoting the kinase state. Our results uphold the view that the linker is endowed with a helix/random coil conformational duality that enables it to behave like a transmission switch, with helix disruption decreasing the kinase/phosphatase activity ratio, as required to modulate the DesK output response.

Reconstruction of perspective shifts and refocusing of a three-dimensional scene from a multi-focus image stack.

The convergence of optical imaging acquisition and image processing algorithms is a fast-evolving interdisciplinary research field focused on the reconstruction of images with novel features of interest. We propose a method for post-capture perspective shift reconstruction (in the x, y, and z directions) of a three-dimensional scene as well as refocusing with apertures of arbitrary shapes and sizes from an optimal multi-focus image stack. The approach is based on the reorganization of the acquired visual information considering a depth-variant point-spread function, which allows it to be applied to strongly defocused multi-focus image stacks. Our method is performed without estimating the depth map or segmenting the in-focus regions. A conventional camera combined with an electrically tunable lens is used for image acquisition and does not require scale transformation or registration between the acquired images. Experimental results for both real and synthetic data images are provided and compared to state-of-the-art schemes.

Image segmentation by nonlinear filtering of optical Hough transform.

The identification and extraction (i.e., segmentation) of geometrical features is crucial in many tasks requiring image analysis. We present a method for the optical segmentation of features of interest from an edge enhanced image. The proposed method is based on the nonlinear filtering (implemented by the use of a spatial light modulator) of the generalized optical Hough transform and is capable of discriminating features by shape and by size. The robustness of the method against noise in the input, low contrast, or overlapping of geometrical features is assessed, and experimental validation of the working principle is presented.