Understanding Racial Inequities in the Implementation of Harm Reduction Initiatives.

Objectives. To elucidate a structurally oriented theoretical framework that considers legacies of racism, trauma, and social exclusion and to interrogate the "unmet obligations" of the institutionalization of the harm reduction infrastructure to provide equitable protections to Black and Latinx people who use drugs (PWUD) in Maryland. Methods. In 2019, we conducted a rapid ethnographic assessment of and qualitative interviews with PWUD (n = 72) and stakeholders (n = 85) in 5 Maryland counties. We assessed PWUD's experiences, service gaps in as well as barriers and facilitators to accessing services, and the potential to expand harm reduction programs. Results. The unmet obligations we found included enforcement and punitive governance of syringes, naloxone, and other drug use equipment; racism and racialization, social exclusion, and legacies of trauma; and differential implications of harm reduction for populations experiencing racialized criminalization. Conclusions. The implementation of harm reduction policies are a first step, but assessment of structural dynamics are needed for diverse communities with unique histories. This research illuminates a key paradox: progressive policy is implemented, yet the overdose crisis escalates in communities where various forms of racialized exclusions are firmly entrenched. (Am J Public Health. 2022;112(S2):S173-S181. https://doi.org/10.2105/AJPH.2022.306767).

Influenza management with new therapies.

PURPOSE OF REVIEW: Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting. RECENT FINDINGS: Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group. SUMMARY: Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.

Artificial intelligence and robotics: a combination that is changing the operating room.

PURPOSE: The aim of the current narrative review was to summarize the available evidence in the literature on artificial intelligence (AI) methods that have been applied during robotic surgery. METHODS: A narrative review of the literature was performed on MEDLINE/Pubmed and Scopus database on the topics of artificial intelligence, autonomous surgery, machine learning, robotic surgery, and surgical navigation, focusing on articles published between January 2015 and June 2019. All available evidences were analyzed and summarized herein after an interactive peer-review process of the panel. LITERATURE REVIEW: The preliminary results of the implementation of AI in clinical setting are encouraging. By providing a readout of the full telemetry and a sophisticated viewing console, robot-assisted surgery can be used to study and refine the application of AI in surgical practice. Machine learning approaches strengthen the feedback regarding surgical skills acquisition, efficiency of the surgical process, surgical guidance and prediction of postoperative outcomes. Tension-sensors on the robotic arms and the integration of augmented reality methods can help enhance the surgical experience and monitor organ movements. CONCLUSIONS: The use of AI in robotic surgery is expected to have a significant impact on future surgical training as well as enhance the surgical experience during a procedure. Both aim to realize precision surgery and thus to increase the quality of the surgical care. Implementation of AI in master-slave robotic surgery may allow for the careful, step-by-step consideration of autonomous robotic surgery.

Developments in Transduction, Connectivity and AI/Machine Learning for Point-of-Care Testing.

We review some emerging trends in transduction, connectivity and data analytics for Point-of-Care Testing (POCT) of infectious and non-communicable diseases. The patient need for POCT is described along with developments in portable diagnostics, specifically in respect of Lab-on-chip and microfluidic systems. We describe some novel electrochemical and photonic systems and the use of mobile phones in terms of hardware components and device connectivity for POCT. Developments in data analytics that are applicable for POCT are described with an overview of data structures and recent AI/Machine learning trends. The most important methodologies of machine learning, including deep learning methods, are summarised. The potential value of trends within POCT systems for clinical diagnostics within Lower Middle Income Countries (LMICs) and the Least Developed Countries (LDCs) are highlighted.

Imaging the Nonlinear Susceptibility Tensor of Collagen by Nonlinear Optical Stokes Ellipsometry.

Nonlinear optical Stokes ellipsometric (NOSE) microscopy was demonstrated for the analysis of collagen-rich biological tissues. NOSE is based on polarization-dependent second harmonic generation imaging. NOSE was used to access the molecular-level distribution of collagen fibril orientation relative to the local fiber axis at every position within the field of view. Fibril tilt-angle distribution was investigated by combining the NOSE measurements with ab initio calculations of the predicted molecular nonlinear optical response of a single collagen triple helix. The results were compared with results obtained previously by scanning electron microscopy, nuclear magnetic resonance imaging, and electron tomography. These results were enabled by first measuring the laboratory-frame Jones nonlinear susceptibility tensor, then extending to the local-frame tensor through pixel-by-pixel corrections based on local orientation.

Guiding synchrotron X-ray diffraction by multimodal video-rate protein crystal imaging.

Synchronous digitization, in which an optical sensor is probed synchronously with the firing of an ultrafast laser, was integrated into an optical imaging station for macromolecular crystal positioning prior to synchrotron X-ray diffraction. Using the synchronous digitization instrument, second-harmonic generation, two-photon-excited fluorescence and bright field by laser transmittance were all acquired simultaneously with perfect image registry at up to video-rate (15 frames s(-1)). A simple change in the incident wavelength enabled simultaneous imaging by two-photon-excited ultraviolet fluorescence, one-photon-excited visible fluorescence and laser transmittance. Development of an analytical model for the signal-to-noise enhancement afforded by synchronous digitization suggests a 15.6-fold improvement over previous photon-counting techniques. This improvement in turn allowed acquisition on nearly an order of magnitude more pixels than the preceding generation of instrumentation and reductions of well over an order of magnitude in image acquisition times. These improvements have allowed detection of protein crystals on the order of 1 µm in thickness under cryogenic conditions in the beamline. These capabilities are well suited to support serial crystallography of crystals approaching 1 µm or less in dimension.

Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance--NO and MMP-9 interactions.

Nitric oxide (NO) and matrix metalloproteinase 9 (MMP-9) levels are found to increase in inflammation states and in cancer, and their levels may be reciprocally modulated. Understanding interactions between NO and MMP-9 is of biological and pharmacological relevance and may prove crucial in designing new therapeutics. The reciprocal interaction between NO and MMP-9 have been studied for nearly twenty years but to our knowledge, are yet to be the subject of a review. This review provides a summary of published data regarding the complex and sometimes contradictory effects of NO on MMP-9. We also analyse molecular mechanisms modulating and mediating NO-MMP-9 interactions. Finally, a potential therapeutic relevance of these interactions is presented.

Video-rate two-photon excited fluorescence lifetime imaging system with interleaved digitization.

A fast (up to video rate) two-photon excited fluorescence lifetime imaging system based on interleaved digitization is demonstrated. The system is compatible with existing beam-scanning microscopes with minor electronics and software modification. Proof-of-concept demonstrations were performed using laser dyes and biological tissue.

Bi- to tetravalent glycoclusters presenting GlcNAc/GalNAc as inhibitors: from plant agglutinins to human macrophage galactose-type lectin (CD301) and galectins.

Emerging insights into the functional spectrum of tissue lectins leads to identification of new targets for the custom-made design of potent inhibitors, providing a challenge for synthetic chemistry. The affinity and selectivity of a carbohydrate ligand for a lectin may immensely be increased by a number of approaches, which includes varying geometrical or topological features. This perspective leads to the design and synthesis of glycoclusters and their testing using assays of physiological relevance. Herein, hydroquinone, resorcinol, benzene-1,3,5-triol and tetra(4-hydroxyphenyl)ethene have been employed as scaffolds and propargyl derivatives obtained. The triazole-containing linker to the α/ß-O/S-glycosides of GlcNAc/GalNAc presented on these scaffolds was generated by copper-catalysed azide-alkyne cycloaddition. This strategy was used to give a panel of nine glycoclusters with bi-, tri- and tetravalency. Maintained activity for lectin binding after conjugation was ascertained for both sugars in solid-phase assays with the plant agglutinins WGA (GlcNAc) and DBA (GalNAc). Absence of cross-reactivity excluded any carbohydrate-independent reactivity of the bivalent compounds, allowing us to proceed to further testing with a biomedically relevant lectin specific for GalNAc. Macrophage galactose(-binding C)-type lectin, involved in immune defence by dendritic cells and in virus uptake, was produced as a soluble protein without/with its α-helical coiled-coil stalk region. Binding to ligands presented on a matrix and on cell surfaces was highly susceptible to the presence of the tetravalent inhibitor derived from the tetraphenylethene-containing scaffold, and presentation of GalNAc with an α-thioglycosidic linkage proved favorable. Cross-reactivity of this glycocluster to human galectins-3 and -4, which interact with Tn-antigen-presenting mucins, was rather small. Evidently, the valency and spatial display of α-GalNAc residues is a key factor to design potent and selective inhibitors for this lectin.

Matrix metalloproteinases in inflammatory bowel disease: an update.

Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.

Mechanisms of platelet-stimulated colon cancer invasion: role of clusterin and thrombospondin 1 in regulation of the P38MAPK-MMP-9 pathway.

Platelets have been implicated in colon cancer metastasis and prognosis but the underlying molecular mechanisms remain unclear. We evaluated the role of the different mitogen-activated protein kinase (MAPK) pathways in platelet-stimulated matrix metalloproteinase-9 (MMP-9) generation and colon cancer invasion. In addition, proteins released during platelet-tumour cell interactions were studied. For this purpose, interactions of Caco-2 and HT29 cells with platelets were studied using scanning electron microscopy, aggregometry, flow cytometry and cell invasion chambers. Quantitative PCR and zymography were used to study MMP-9 gene expression and activity, respectively, whereas western blot was used to study p38MAPK. Finally, the origin of proteins during platelet-cancer cell interactions was investigated using stable isotope labelling by amino acids in cell culture (SILAC)-based proteomics. We found that platelets promoted p38MAPK phosphorylation and MMP-9 up-regulation in both cell lines, with the subsequent cell-invasion-promoting effects. Pharmacological inhibition of p38MAPK led to a significant down-regulation of MMP-9 and colon cancer cell invasiveness. Also, p38MAPK-small interfering RNA abolished the induction of platelet-stimulated MMP-9. SILAC experiments demonstrated that thrombospondin 1 (TSP1) was released mainly from platelets and clusterin by both platelets and cancer cells. Finally, inhibition of TSP1 and clusterin abolished p38MAPK phosphorylation, MMP-9 activity and platelet-stimulated colon cancer invasion. Our results indicate that platelet-secreted TSP1 and clusterin promote the signal regulation of MMP-9 in platelet-induced colonic cancer invasion via a P38MAPK-regulated pathway. These findings are relevant to the development of therapeutic approaches to preventing and reducing tumour cell metastasis induced by colon adenocarcinoma.

Kinetic trapping of metastable amino acid polymorphs.

Second harmonic generation (SHG) microscopy measurements indicate that inkjet-printed racemic solutions of amino acids can produce nanocrystals trapped in metastable polymorph forms upon rapid solvent evaporation. Polymorphism impacts the composition, distribution, and physico-kinetic properties of organic solids, with energetic arguments favoring the most stable polymorph. In this study, unfavored noncentrosymmetric crystal forms were observed by SHG microscopy. Polarization-dependent SHG measurement and synchrotron X-ray microdiffraction analysis of individual printed drops are consistent with formation of homochiral crystal production. Fundamentally, these results provide evidence supporting the ubiquity of Ostwald's Rule of Stages, describing the hypothesized transitioning of crystals between metastable polymorphic forms in the early stages of crystal formation. Practically, the presence of homochiral metastable forms has implications on chiral resolution and on solid form preparations relying on rapid solvent evaporation.

Digital deconvolution filter derived from linear discriminant analysis and application for multiphoton fluorescence microscopy.

A digital filter derived from linear discriminant analysis (LDA) is developed for recovering impulse responses in photon counting from a high speed photodetector (rise time of ~1 ns) and applied to remove ringing distortions from impedance mismatch in multiphoton fluorescence microscopy. Training of the digital filter was achieved by defining temporally coincident and noncoincident transients and identifying the projection within filter-space that best separated the two classes. Once trained, data analysis by digital filtering can be performed quickly. Assessment of the reliability of the approach was performed through comparisons of simulated voltage transients, in which the ground truth results were known a priori. The LDA filter was also found to recover deconvolved impulses for single photon counting from highly distorted ringing waveforms from an impedance mismatched photomultiplier tube. The LDA filter was successful in removing these ringing distortions from two-photon excited fluorescence micrographs and through data simulations was found to extend the dynamic range of photon counting by approximately 3 orders of magnitude through minimization of detector paralysis.

Polarization-modulated second harmonic generation ellipsometric microscopy at video rate.

Fast 8 MHz polarization modulation coupled with analytical modeling, fast beam-scanning, and synchronous digitization (SD) have enabled simultaneous nonlinear optical Stokes ellipsometry (NOSE) and polarized laser transmittance imaging with image acquisition rates up to video rate. In contrast to polarimetry, in which the polarization state of the exiting beam is recorded, NOSE enables recovery of the complex-valued Jones tensor of the sample that describes all polarization-dependent observables of the measurement. Every video-rate scan produces a set of 30 images (10 for each detector with three detectors operating in parallel), each of which corresponds to a different polarization-dependent result. Linear fitting of this image set contracts it down to a set of five parameters for each detector in second harmonic generation (SHG) and three parameters for the transmittance of the incident beam. These parameters can in turn be used to recover the Jones tensor elements of the sample. Following validation of the approach using z-cut quartz, NOSE microscopy was performed for microcrystals of both naproxen and glucose isomerase. When weighted by the measurement time, NOSE microscopy was found to provide a substantial (>7 decades) improvement in the signal-to-noise ratio relative to our previous measurements based on the rotation of optical elements and a 3-fold improvement relative to previous single-point NOSE approaches.

Linear fitting of multi-threshold counting data with a pixel-array detector for spectral X-ray imaging.

Experiments and modeling are described to perform spectral fitting of multi-threshold counting measurements on a pixel-array detector. An analytical model was developed for describing the probability density function of detected voltage in X-ray photon-counting arrays, utilizing fractional photon counting to account for edge/corner effects from voltage plumes that spread across multiple pixels. Each pixel was mathematically calibrated by fitting the detected voltage distributions to the model at both 13.5 keV and 15.0 keV X-ray energies. The model and established pixel responses were then exploited to statistically recover images of X-ray intensity as a function of X-ray energy in a simulated multi-wavelength and multi-counting threshold experiment.

High frame-rate multichannel beam-scanning microscopy based on Lissajous trajectories.

A simple beam-scanning optical design based on Lissajous trajectory imaging is described for achieving up to kHz frame-rate optical imaging on multiple simultaneous data acquisition channels. In brief, two fast-scan resonant mirrors direct the optical beam on a circuitous trajectory through the field of view, with the trajectory repeat-time given by the least common multiplier of the mirror periods. Dicing the raw time-domain data into sub-trajectories combined with model-based image reconstruction (MBIR) 3D in-painting algorithms allows for effective frame-rates much higher than the repeat time of the Lissajous trajectory. Since sub-trajectory and full-trajectory imaging are simply different methods of analyzing the same data, both high-frame rate images with relatively low resolution and low frame rate images with high resolution are simultaneously acquired. The optical hardware required to perform Lissajous imaging represents only a minor modification to established beam-scanning hardware, combined with additional control and data acquisition electronics. Preliminary studies based on laser transmittance imaging and polarization-dependent second harmonic generation microscopy support the viability of the approach both for detection of subtle changes in large signals and for trace-light detection of transient fluctuations.

Carcinoid Heart Disease and a Complicated Course of Progressive Gastroenteropancreatic Neuroendocrine Neoplasia: A Case Report.

Introduction: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are a relatively rare, heterogenous group of malignancies originating from secretory cells of the neuroendocrine system. Carcinoid syndrome is a complication of neuroendocrine tumours, characterized by a triad of flushing, bronchospasm, and diarrhoea. This is due to the release of serotonin and other vasoactive substances by the tumour. Elevated levels of serotonin can also cause fibrotic changes in the structures of the heart, which can lead to cardiac complications termed carcinoid heart disease. We report the case of a 64-year-old man diagnosed with carcinoid heart disease 19 years after his initial diagnosis of grade 2 GEP-NET with liver metastases. Case Presentation: The patient presented with symptoms of shortness of breath, lower limb swelling, abdominal swelling, and chest pain. He was on treatment with subcutaneous lanreotide 120 mg twice weekly prior to admission. An echocardiogram showed moderate tricuspid regurgitation and mitral regurgitation but preserved left ventricular systolic function, consistent with right heart failure. A CT pulmonary angiogram showed a small volume left lingula pulmonary embolism with bilateral pleural effusions and stable pericardial effusion with evidence of right ventricular strain. The patient was started on IV furosemide 40 mg twice daily, SC octreotide 100 µg three times daily, and therapeutic tinzaparin. The patient was discharged following successful diuresis. Conclusion: This case report highlights the importance of regular echocardiogram and cardiovascular checkups in patients with carcinoid tumours and liver metastases. A multidisciplinary approach involving medical oncologists, cardiothoracic surgeons, and cardiologists is vital in ensuring early treatment and preventing late-stage complications of carcinoid heart disease.

The underuse of AI in the health sector: Opportunity costs, success stories, risks and recommendations.

Purpose: This contribution explores the underuse of artificial intelligence (AI) in the health sector, what this means for practice, and how much the underuse can cost. Attention is drawn to the relevance of an issue that the European Parliament has outlined as a "major threat" in 2020. At its heart is the risk that research and development on trusted AI systems for medicine and digital health will pile up in lab centers without generating further practical relevance. Our analysis highlights why researchers, practitioners and especially policymakers, should pay attention to this phenomenon. Methods: The paper examines the ways in which governments and public agencies are addressing the underuse of AI. As governments and international organizations often acknowledge the limitations of their own initiatives, the contribution explores the causes of the current issues and suggests ways to improve initiatives for digital health. Results: Recommendations address the development of standards, models of regulatory governance, assessment of the opportunity costs of underuse of technology, and the urgency of the problem. Conclusions: The exponential pace of AI advances and innovations makes the risks of underuse of AI increasingly threatening.

Polarization-resolved second-harmonic generation microscopy as a method to visualize protein-crystal domains.

Polarization-resolved second-harmonic generation (PR-SHG) microscopy is described and applied to identify the presence of multiple crystallographic domains within protein-crystal conglomerates, which was confirmed by synchrotron X-ray diffraction. Principal component analysis (PCA) of PR-SHG images resulted in principal component 2 (PC2) images with areas of contrasting negative and positive values for conglomerated crystals and PC2 images exhibiting uniformly positive or uniformly negative values for single crystals. Qualitative assessment of PC2 images allowed the identification of domains of different internal ordering within protein-crystal samples as well as differentiation between multi-domain conglomerated crystals and single crystals. PR-SHG assessments of crystalline domains were in good agreement with spatially resolved synchrotron X-ray diffraction measurements. These results have implications for improving the productive throughput of protein structure determination through early identification of multi-domain crystals.

Impact of a surfactant on the electroactivity of proteins at an aqueous-organogel microinterface array.

The impact of surfactant addition to the organic phase on the electroactivity of proteins at the aqueous-organogel interface was examined by voltammetry. The presence of bis(2-ethylhexyl)sulfosuccinate (AOT) in the organogel phase, as the sodium salt, caused marked changes in the peak currents for myoglobin detection. The protein desorption voltammetric peak exhibited a 6-fold increase in the current compared to the corresponding experiment without surfactant. Interfacial coverage showed a 17-fold increase in the adsorbed protein at the interface, from 50 pmol cm(-2), in the absence of surfactant, to 850 pmol cm(-2), in the presence of 10 mM surfactant. Additionally, the presence of the surfactant resulted in a second pair of adsorption/desorption peaks at lower potentials and in a change in the capacitance of the system. The formation of surfactant-protein and surfactant-protein-organic anion deposits is proposed on the basis of these features, leading to increased voltammetric signals for myoglobin, hemoglobin, and cytochrome c. The mechanism of protein-surfactant interaction was probed by using the surfactant as the anion in the organic phase electrolyte salt. Repetitive cyclic voltammetry of cytochrome c showed that in the presence of surfactant there was an enhancement of the signal, caused by a buildup of the protein-surfactant-electrolyte anion assembly at the interface. These findings provide the basis for surfactant-modified interfaces to enhance the electroanalytical performance for protein detection.