Predictors of outcomes in emergency department patients with suspected infections and without fulfillment of the sepsis criteria.

BACKGROUND: Data on patient characteristics and determinants of serious outcomes for acutely admitted patients with infections who do not fulfill the sepsis criteria are sparse. The study aimed to characterize acutely admitted emergency department (ED) patients with infections and a composite outcome of in-hospital mortality or transfer to the intensive care unit without fulfilling the criteria for sepsis and to examine predictors of the composite outcome. METHODS: This was a secondary analysis of data from a prospective observational study of patients with suspected bacterial infection admitted to the ED between October 1, 2017 and March 31, 2018. A National Early Warning Score 2 (NEWS2) ≥ 5 within the first 4 h in the ED was assumed to represent a sepsis-like condition with a high risk for the composite endpoint. Patients who achieved the composite outcome were grouped according to fulfillment of the NEWS2 ≥ 5 criteria. We used logistic regression analysis to estimate the unadjusted and adjusted odds ratio (OR) for the composite endpoint among patients with either NEWS2  < 5 (NEWS2-) or NEWS2  ≥ 5 (NEWS2+). RESULTS: A total of 2055 patients with a median age of 73 years were included. Of these, 198 (9.6%) achieved the composite endpoint, including 59 (29.8%) NEWS2- and 139 (70.2%) NEWS2+ patients, respectively. Diabetes (OR 2.23;1.23-4.0), a Sequential Organ Failure Assessment (SOFA) score ≥ 2 (OR 2.57;1.37-4.79), and a Do-not-attempt-cardiopulmonary-resuscitation order (DNACPR) on admission (OR 3.70;1.75-7.79) were independent predictive variables for the composite endpoint in NEWS2- patients (goodness-of-fit test P = 0.291; area under the receiver operating characteristic curve for the model (AUROC) = 0.72). The regression model for NEWS2+ patients revealed that a SOFA score ≥ 2 (OR 2.79; 1.59-4.91), hypothermia (OR 2.48;1.30-4.75), and DNACPR order on admission were predictive variables for the composite endpoint (goodness-of-fit test P = 0.62; AUROC for the model = 0.70). CONCLUSION: Approximately one-third of the patients with infections and serious outcomes during hospitalization did not meet the NEWS2 threshold for likely sepsis. Our study identified factors with independent predictive values for the development of serious outcomes that should be tested in future prediction models.

The Classification Power of Classical and Intra-voxel Incoherent Motion (IVIM) Fitting Models of Diffusion-weighted Magnetic Resonance Images: An Experimental Study.

This study aims at investigating the classification power of different b-values of the diffusion-weighted magnetic resonance images (DWI) as indicator of prostate cancer. This paper investigates several techniques for analyzing data from DWI acquired at a range of b-values for the purpose of detecting prostate cancer. In the first phase of experiments, we analyze the available data by producing two main parametric maps using two common models, namely: the intra-voxel incoherent motion (IVIM) model and the mono-exponential ADC model. Accordingly, we evaluated the benign/malignant tissue classification potential of several parametric maps produced using different combinations of b-values and fitting models. In the second phase, we utilized the maps that performed best in the first phase of experiments to design a machine learning-based computer-assisted diagnosis system for the detection of early stage prostate cancer. The system performance was cross-validated using data from 20 patients. On a fivefold cross-validation scheme, a maximum accuracy and an area under the receiver operating characteristic (AUC) of 90% and 0.978, respectively, was achieved by a system that uses ADC maps fitted using the mono-exponential model at 11 different b-values. The results suggest that the proposed machine learning-based diagnosis system is potentially powerful in differentiating between malignant and benign prostate tissues when combined with carefully generated ADC maps.

From letters to composed concepts: A magnetoencephalography study of reading.

Language comprehension requires the recognition of individual words and the combination of their meanings to yield complex concepts or interpretations. This combinatory process often requires the insertion of unstated semantic material between words, based on thematic or feature knowledge. For example, the phrase horse barn is not interpreted as a blend of a horse and a barn, but specifically a barn where horses are kept. Previous neuroscientific evidence suggests that left posterior and anterior temporal cortex underpin thematic and feature-based concept knowledge, respectively, but much remains unclear about how these areas contribute to combinatory language processing. Using magnetoencephalography, we contrasted source-localized responses to modifier-noun phrases involving thematic relations versus feature modifications, while also examining how lower-level orthographic processing fed composition. Participants completed three procedures examining responses to letter-strings, adjective-noun phrases, and noun-noun combinations that varied the semantic relations between words. We found that sections of the left anterior temporal lobe, posterior temporal lobe, and cortex surrounding the angular gyrus were all engaged in the minimal composition of adjective-noun phrases, a more distributed network than in most prior studies of minimal composition. Of these regions, only the left posterior temporal lobe was additionally sensitive to implicit thematic relations between composing words, suggesting that it houses a specialized relational processing component in a wider composition network. We additionally identified a left occipitotemporal progression from orthographic to lexical processing, feeding ventral anterior areas engaged in the combination of word meanings. Finally, by examining source signal leakage, we characterized the degree to which these responses could be distinguished from one another using source estimation.

Covalent Organic Framework Embedded with Magnetic Nanoparticles for MRI and Chemo-Thermotherapy.

Nanoscale imine-linked covalent organic frameworks (nCOFs) were first loaded with the anticancer drug Doxorubicin (Dox), coated with magnetic iron oxide nanoparticles (γ-Fe2O3 NPs), and stabilized with a shell of poly(l-lysine) cationic polymer (PLL) for simultaneous synergistic thermo-chemotherapy treatment and MRI imaging. The pH responsivity of the resulting nanoagents (γ-SD/PLL) allowed the release of the drug selectively within the acidic microenvironment of late endosomes and lysosomes of cancer cells (pH 5.4) and not in physiological conditions (pH 7.4). γ-SD/PLL could efficiently generate high heat (48 °C) upon exposure to an alternating magnetic field due to the nCOF porous structure that facilitates the heat conduction, making γ-SD/PLL excellent heat mediators in an aqueous solution. The drug-loaded magnetic nCOF composites were cytotoxic due to the synergistic toxicity of Dox and the effects of hyperthermia in vitro on glioblastoma U251-MG cells and in vivo on zebrafish embryos, but they were not significantly toxic to noncancerous cells (HEK293). To the best of our knowledge, this is the first report of multimodal MRI probe and chemo-thermotherapeutic magnetic nCOF composites.

Susceptibility of Primary Sensory Cortex to Spreading Depolarizations.

UNLABELLED: Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT: Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury.

Orientation dependence of microcirculation-induced diffusion signal in anisotropic tissues.

PURPOSE: To seek a better understanding of the effect of organized capillary flow on the MR diffusion-weighted signal. METHODS: A theoretical framework was proposed to describe the diffusion-weighted MR signal, which was then validated both numerically using a realistic model of capillary network and experimentally in an animal model of isolated perfused heart preparation with myocardial blood flow verified by means of direct arterial spin labeling measurements. RESULTS: Microcirculation in organized tissues gave rise to an MR signal that could be described as a combination of the bi-exponential behavior of conventional intravoxel incoherent motion (IVIM) theory and diffusion tensor imaging (DTI) -like anisotropy of the vascular signal, with the flow-related pseudo diffusivity represented as the linear algebraic product between the encoding directional unit vector and an appropriate tensor entity. Very good agreement between theoretical predictions and both numerical and experimental observations were found. CONCLUSION: These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues. Magn Reson Med 76:1252-1262, 2016. © 2015 Wiley Periodicals, Inc.

Diffusion tensor imaging and histology of developing hearts.

Diffusion tensor imaging (DTI) has emerged as a promising method for noninvasive quantification of myocardial microstructure. However, the origin and behavior of DTI measurements during myocardial normal development and remodeling remain poorly understood. In this work, conventional and bicompartmental DTI in addition to three-dimensional histological correlation were performed in a sheep model of myocardial development from third trimester to postnatal 5 months of age. Comparing the earliest time points in the third trimester with the postnatal 5 month group, the scalar transverse diffusivities preferentially increased in both left ventricle (LV) and right ventricle (RV): secondary eigenvalues D2 increased by 54% (LV) and 36% (RV), whereas tertiary eigenvalues D3 increased by 85% (LV) and 67% (RV). The longitudinal diffusivity D1 changes were small, which led to a decrease in fractional anisotropy by 41% (LV) and 33% (RV) in 5 month versus fetal hearts. Histological analysis suggested that myocardial development is associated with hyperplasia in the early stages of the third trimester followed by myocyte growth in the later stages up to 5 months of age (increased average myocyte width by 198%, myocyte length by 128%, and decreased nucleus density by 70% between preterm and postnatal 5 month hearts.) In a few histological samples (N = 6), correlations were observed between DTI longitudinal diffusivity and myocyte length (r = 0.86, P < 0.05), and transverse diffusivity and myocyte width (r = 0.96, P < 0.01). Linear regression analysis showed that transverse diffusivities are more affected by changes in myocyte size and nucleus density changes than longitudinal diffusivities, which is consistent with predictions of classical models of diffusion in porous media. Furthermore, primary and secondary DTI eigenvectors during development changed significantly. Collectively, the findings demonstrate a role for DTI to monitor and quantify myocardial development, and potentially cardiac disease. Copyright © 2016 John Wiley & Sons, Ltd.

OKN-007 decreases tumor necrosis and tumor cell proliferation and increases apoptosis in a preclinical F98 rat glioma model.

BACKGROUND: Glioblastoma is a malignant World Health Organization (WHO) grade IV glioma with a poor prognosis in humans. New therapeutics are desperately required. The nitrone OKN-007 (2,4-disulfophenyl-PBN) has demonstrated effective anti-glioma properties in several rodent models and is currently being used as a clinical investigational drug for recurrent gliomas. We assessed the regional effects of OKN-007 in the tumor necrotic core and non-necrotic tumor parenchyma. METHODS: An F98 rat glioma model was evaluated using proton magnetic resonance spectroscopy ((1) H-MRS), diffusion-weighted imaging (DWI), morphological T2-weighted imaging (T2W) at 7 Tesla (30 cm-bore MRI), as well as immunohistochemistry and microarray assessments, at maximum tumor volumes (15-23 days following cell implantation in untreated (UT) tumors, and 18-35 days in OKN-007-treated tumors). RESULTS: (1) H-MRS data indicates that Lip0.9/Cho, Lip0.9/Cr, Lip1.3/Cho, and Lip1.3/Cr ratios are significantly decreased (all P < 0.05) in the OKN-007-treated group compared with UT F98 gliomas. The Cho/Cr ratio is also significantly decreased in the OKN-007-treated group compared with UT gliomas. In addition, the OKN-007-treated group demonstrates significantly lower ADC values in the necrotic tumor core and the nonnecrotic tumor parenchyma (both P < 0.05) compared with the UT group. There was also an increase in apoptosis following OKN-007 treatment (P < 0.01) compared with UT. CONCLUSION: OKN-007 reduces both necrosis and tumor cell proliferation, as well as seems to mediate multiple effects in different tumor regions (tumor necrotic core and nonnecrotic tumor parenchyma) in F98 gliomas, indicating the efficacy of OKN-007 as an anti-cancer agent and its potential clinical use.

Animal model of reversible, right ventricular failure.

BACKGROUND: Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. MATERIALS AND METHODS: Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. RESULTS: RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 µL ± 123 for control, 2381 µL ± 637 for RVF, and 635 µL ± 549 for RVR, and RV wall thicknesses were 0.98 mm ± 0.12 for controls (P = 0.05), 1.72 mm ± 0.60 for RVF, and 1.16 mm ± 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. CONCLUSIONS: We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans.

Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation.

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy (n = 14) and from normal donors (n = 5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1 ), secondary (D2 ) and tertiary (D3 ) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were -0.51, 0.59, 0.56 and 0.62 (P < 0.05), respectively. The correlation between D1 and collagen content was not significant (r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts.

Decorin prevents the development of juvenile communicating hydrocephalus.

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-ß has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-ß antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-ß/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-ß1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-ß-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.

Differential vulnerability of white matter structures to experimental infantile hydrocephalus detected by diffusion tensor imaging.

PURPOSE: The differential vulnerability of white matter (WM) to acute and chronic infantile hydrocephalus and the related effects of early and late reservoir treatment are unknown, but diffusion tensor imaging (DTI) could provide this information. Thus, we characterized WM integrity using DTI in a clinically relevant model. METHODS: Obstructive hydrocephalus was induced in 2-week-old felines by intracisternal kaolin injection. Ventricular reservoirs were placed 1 (early) or 2 (late) weeks post-kaolin and tapped frequently based solely on neurological deficit. Hydrocephalic and age-matched control animals were sacrificed 12 weeks postreservoir. WM integrity was evaluated in the optic system, corpus callosum, and internal capsule prereservoir and every 3 weeks using DTI. Analyses were grouped as acute (<6 weeks) or chronic (≥6 weeks). RESULTS: In the corpus callosum during acute stages, fractional anisotropy (FA) decreased significantly with early and late reservoir placement (p = 0.0008 and 0.0008, respectively), and diffusivity increased significantly in early (axial, radial, and mean diffusivity, p = 0.0026, 0.0012, and 0.0002, respectively) and late (radial and mean diffusivity, p = 0.01 and 0.0038, respectively) groups. Chronically, the corpus callosum was thinned and not detectable by DTI. FA was significantly lower in the optic chiasm and tracts (p = 0.0496 and 0.0052, respectively) with late but not early reservoir placement. In the internal capsule, FA in both reservoir groups increased significantly with age (p < 0.05) but diffusivity remained unchanged. CONCLUSIONS: All hydrocephalic animals treated with intermittent ventricular reservoir tapping demonstrated progressive ventriculomegaly. Both reservoir groups demonstrated WM integrity loss, with the CC the most vulnerable and the optic system the most resilient.

Coral reef aorta: a rare form of obstruction of the ascending aorta in adolescent with aortopathy- case report.

BACKGROUND: Supra aortic obstruction in children is uncommon and is seen in certain unique conditions. While intraluminal obstruction due to heavy calcification is seen in older populations, it is not described in pediatric populations. The coral reef aorta is a rare and distinct calcifying disease causing luminal obstruction of the suprarenal aorta in adults. The definition of this diagnosis relies entirely on the unique aspects and consistency of the lesions, which are rock-hard, irregular, gritty plaques with a white luminal surface resembling a coral reef. However, no such case has been described in children. CASE PRESENTATION: We present an adolescent boy who presented with a heavily calcified ascending aortic lesion associated with aortopathy and hypertension, 12 years after an aortic coarctation repair. The investigations included echocardiography, magnetic resonance and computer-tomographic imaging. A 3-D model was printed in order to visualize and plan surgical steps in advance for safe placement of clamps and defining the extent of resection. In addition, it provided an idea about tissue quality, thickness, spatial relationship, and orientation in relation to surrounding structures. Successful resection and replacement of the diseased segment of the aorta were achieved on cardiopulmonary bypass support. Post-operative recovery was uneventful, and at 6-month follow-up, the patient is doing well. In this report, various aspects of such lesions have been discussed, including clinical presentations, complications, planning and conduct of a safe cardiopulmonary bypass, and precautions during surgery for a successful outcome. CONCLUSION: Complicated obstructive aortic lesions in children require careful assessment, appropriate advanced imaging, and the use of 3-D printing technology in order to plan and perform safe and effective surgical management. The etiology of severe calcified aorta in children may be related to metabolic factors, previous surgery, use of a homograft, or an inflammatory process. However, it has yet to be proven.

Resveratrol Attenuates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Induction of Myeloid-Derived Suppressor Cells (MDSC) and Their Functions.

Previously, we showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) ligand and a potent and persistent toxicant and carcinogenic agent, induces high levels of murine myeloid-derived suppressor cell (MDSC) when injected into mice. In the current study, we demonstrate that Resveratrol (3,4,5-trihydroxy-trans-stilbene; RSV), an AhR antagonist, reduces TCDD-mediated MDSC induction. RSV decreased the number of MDSCs induced by TCDD in mice but also mitigated the immunosuppressive function of TCDD-induced MDSCs. TCDD caused a decrease in F4/80+ macrophages and an increase in CD11C+ dendritic cells, while RSV reversed these effects. TCDD caused upregulation in CXCR2, a critical molecule involved in TCDD-mediated induction of MDSCs, and Arginase-1 (ARG-1), involved in the immunosuppressive functions of MDSCs, while RSV reversed this effect. Transcriptome analysis of Gr1+ MDSCs showed an increased gene expression profile involved in the metabolic pathways in mice exposed to TCDD while RSV-treated mice showed a decrease in such pathways. The bio-energetic profile of these cells showed that RSV treatment decreased the energetic demands induced by TCDD. Overall, the data demonstrated that RSV decreased TCDD-induced MDSC induction and function by altering the dynamics of various myeloid cell populations involving their numbers, phenotype, and immunosuppressive potency. Because MDSCs play a critical role in tumor growth and metastasis, our studies also support the potential use of RSV to attenuate the immunosuppressive properties of MDSC.

pH-Responsive Upconversion Mesoporous Silica Nanospheres for Combined Multimodal Diagnostic Imaging and Targeted Photodynamic and Photothermal Cancer Therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF4:Yb/Er/Gd,Bi2Se3) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF4:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while Bi2Se3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects in vitro and in vivo via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

pH-responsive upconversion mesoporous silica nanospheres for combined multimodal diagnostic imaging and targeted photodynamic and photothermal cancer therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have garnered considerable interest as non-invasive cancer treatment modalities. However, these approaches remain limited by low solubility, poor stability and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome these limitations, we have designed biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium and gadolinium) and bismuth selenide (NaYF 4 :Yb/Er/Gd,Bi 2 Se 3 ) within a mesoporous silica shell that encapsulates a PS, Chlorin e6 (Ce6), in its pores. NaYF 4 :Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites the Ce6 to generate cytotoxic reactive oxygen species (ROS), while the PTA Bi 2 Se 3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging (MRI) of the nanospheres. The mesoporous silica shell is coated with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG) to ensure retention of the encapsulated Ce6 and minimize interactions with serum proteins and macrophages that impede tumor targeting. Finally, the coat is functionalized with the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into cancer cells within the mildly acidic tumor microenvironment. Following uptake by cancer cells in vitro , NIR laser irradiation of the nanospheres caused substantial cytotoxicity due to ROS production and hyperthermia. The nanospheres facilitated tumor MRI and thermal imaging, and exhibited potent NIR laser light-induced antitumor effects in vivo via combined PDT and PTT, with no observable toxicity to healthy tissue, thereby substantially prolonging survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

Captagone & Morbid Jealousy.

This study aimed to explore the relationship between Captagon usage and the development of delusions of infidelity. The study sample; 101 male patients, was recruited from patients admitted to Eradah Complex for Mental Health and addiction, Jeddah, Saudi Arabia, with the diagnosis of amphetamine (Captagon) induced psychosis during the period from September 2021 to March 2022. All patients underwent an extensive psychiatric interview; including interview with patients' families; a demographic sheet, a drug use questionnaire, the structured clinical interview for DSM-IV (SCID 1), routine medical investigation, and urine screening for drugs. Patients' ages ranged from 19 to 46 years old with Mean ± SD 30.87 ± 6.58. 57.4 % were single, 77.2% have finished their high school, and 22.8% had no work. Captagon using age ranged from 14-40 years old, and regular daily dose ranged from 1-15 tablet, while maximum daily dose ranged from 2-25 tablets. Twenty-six patients (25.7%) of the study group have developed infidelity delusions. A higher divorce rate was present among patients who developed infidelity delusions (53.8%) in comparison to patients who developed other types of delusions (6.7%). Infidelity delusions are common among patients diagnosed with Captagon induce psychosis, and they harmfully influence their social lives.

Percutaneous endoscopic gastrostomy in children: A tertiary center experience.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a common procedure in children. The outcomes of PEG could be affected by the associated disease. We aimed to evaluate the outcomes and safety of PEG tube placement in a tertiary care center with special attention to patients with cardiac disease, ventriculoperitoneal (VP) shunt, or peritoneal dialysis (PD) catheter. METHODS: This retrospective study included 113 pediatric patients who had PEG tube insertion from 2011 to 2021. Eighteen patients (15.93%) had cardiac disease, five patients (4.42%) had PD catheters, and three patients (2.65%) had VP shunt. RESULTS: The median age was 3 years (interquartile range: 1-6), and females represented 55% of our patients. The weight ranged from 2.57 to 60 kg, and the most common indication for insertion was neurological disease (n = 56; 49.56%). The median operative time was 30 (20-45) minutes. Pneumonia and vomiting were the most frequent complications (n = 20, 17.7%). Thirty-day mortality occurred in four patients (3.54%) and 1-year mortality in 10 patients (8.85%). Nine patients (7.96%) required fundoplication, and four patients (3.53%) had tube removal and reinsertion. There was no association between weight and postoperative complications (odds ratio: 0.97; P = .48). There were no differences in postoperative complications among patients with cardiac diseases, PD catheters, and VP shunts. No complications were reported in patients with VP shunt. One patient with cardiac disease and one patient with PD catheter required fundoplication. Removal and reinsertion were needed in one patient with a PD catheter. CONCLUSION: PEG is feasible in low-weight infants with a low complication rate. The complication rate is low in patients with VP shunt, PD catheter, and cardiac patients.

Sleep Deprivation & Amphetamine Induced Psychosis.

Objectives: To explore the relationship between sleep deprivation and amphetamine-induced psychosis. Methods: The patient group included 78 patients with a diagnosis of amphetamine (Captagon)-induced psychosis. The control group included 49 patients with no current or past history of amphetamine (Captagon)-induced psychosis. All study subjects underwent the following: a demographic sheet, a structured clinical interview for SM-IV (SCID 1), a drug use questionnaire, a questionnaire to explore any relationship between sleep deprivation and Captagon-induced psychosis, routine medical investigation, and urine screening for detection of drugs. Results: The patient group showed significantly higher both regular and maximum daily doses of Captagon. Patients showed more periods of sleep deprivation with the use of Captagon in comparison to controls, especially with the increase of the Captagon dose. Patients believed that the occurrence and termination of sleep deprivation were the cause of the start and end of psychotic experiences (more so than the increase and decrease or stoppage of Captagon doses). Conclusion: sleep deprivation plays an essential role in the development of psychotic symptoms in patients who are using Captagon.

Three-Dimensional Virtual and Printed Prototypes in Complex Congenital and Pediatric Cardiac Surgery-A Multidisciplinary Team-Learning Experience.

Three-dimensional (3D) virtual modeling and printing advances individualized medicine and surgery. In congenital cardiac surgery, 3D virtual models and printed prototypes offer advantages of better understanding of complex anatomy, hands-on preoperative surgical planning and emulation, and improved communication within the multidisciplinary team and to patients. We report our single center team-learning experience about the realization and validation of possible clinical benefits of 3D-printed models in surgical planning of complex congenital cardiac surgery. CT-angiography raw data were segmented into 3D-virtual models of the heart-great vessels. Prototypes were 3D-printed as rigid "blood-volume" and flexible "hollow". The accuracy of the models was evaluated intraoperatively. Production steps were realized in the framework of a clinical/research partnership. We produced 3D prototypes of the heart-great vessels for 15 case scenarios (nine males, median age: 11 months) undergoing complex intracardiac repairs. Parity between 3D models and intraoperative structures was within 1 mm range. Models refined diagnostics in 13/15, provided new anatomic information in 9/15. As a team-learning experience, all complex staged redo-operations (13/15; Aristotle-score mean: 10.64 ± 1.95) were rehearsed on the 3D models preoperatively. 3D-printed prototypes significantly contributed to an improved/alternative operative plan on the surgical approach, modification of intracardiac repair in 13/15. No operative morbidity/mortality occurred. Our clinical/research partnership provided coverage for the extra time/labor and material/machinery not financed by insurance. 3D-printed models provided a team-learning experience and contributed to the safety of complex congenital cardiac surgeries. A clinical/research partnership may open avenues for bioprinting of patient-specific implants.