Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Decoding functional hematopoietic progenitor cells in the adult human lung.

The bone marrow is the main site of blood cell production in adults, however, rare pools of hematopoietic stem and progenitor cells with self-renewal and differentiation potential have been found in extramedullary organs. The lung is primarily known for its role in gas exchange but has recently been described as a site of blood production in mice. Here, we show that functional hematopoietic precursors reside in the extravascular spaces of the human lung, at a frequency similar to the bone marrow, and are capable of proliferation and engraftment. The organ-specific gene signature of pulmonary and medullary CD34+ hematopoietic progenitors indicates greater baseline activation of immune, megakaryocyte/platelet and erythroid-related pathways in lung progenitors. Spatial transcriptomics mapped blood progenitors in the lung to a vascular-rich alveolar interstitium niche. These results identify the lung as a pool for uniquely programmed blood stem and progenitor cells with the potential to support hematopoiesis in humans.

Cyclone: an accessible pipeline to analyze, evaluate, and optimize multiparametric cytometry data.

In the past decade, high-dimensional single-cell technologies have revolutionized basic and translational immunology research and are now a key element of the toolbox used by scientists to study the immune system. However, analysis of the data generated by these approaches often requires clustering algorithms and dimensionality reduction representation, which are computationally intense and difficult to evaluate and optimize. Here, we present Cytometry Clustering Optimization and Evaluation (Cyclone), an analysis pipeline integrating dimensionality reduction, clustering, evaluation, and optimization of clustering resolution, and downstream visualization tools facilitating the analysis of a wide range of cytometry data. We benchmarked and validated Cyclone on mass cytometry (CyTOF), full-spectrum fluorescence-based cytometry, and multiplexed immunofluorescence (IF) in a variety of biological contexts, including infectious diseases and cancer. In each instance, Cyclone not only recapitulates gold standard immune cell identification but also enables the unsupervised identification of lymphocytes and mononuclear phagocyte subsets that are associated with distinct biological features. Altogether, the Cyclone pipeline is a versatile and accessible pipeline for performing, optimizing, and evaluating clustering on a variety of cytometry datasets, which will further power immunology research and provide a scaffold for biological discovery.

The symmetric and asymmetric effects of climate change on rice productivity in Malaysia.

The current study aims to examine the symmetric and asymmetric effects of climate change (CC) on rice productivity (RP) in Malaysia. The Autoregressive-Distributed Lag (ARDL) and Non-linear Autoregressive Distributed Lag (NARDL) models were employed in this study. Time series data from 1980 to 2019 were collected from the World Bank and the Department of Statistics, Malaysia. The estimated results are also validated using Fully Modified Ordinary Least Squares (FMOLS), Dynamic Ordinary Least Squares (DOLS), and Canonical Cointegration Regression (CCR). The findings of symmetric ARDL show that rainfall and cultivated area have significant and advantageous effects on rice output. The NARDL-bound test outcomes display that climate change has an asymmetrical long-run impact on rice productivity. Climate change has had varying degrees of positive and negative impacts on rice productivity in Malaysia. Positive changes in temperature and rainfall have a substantial and destructive impact on RP. At the same time, negative variations in temperature and rainfall have a substantial and positive impact on rice production in the Malaysian agriculture sector. Changes in cultivated areas, both positive and negative, have a long-term optimistic impact on rice output. Additionally, we discovered that only temperature affects rice output in both directions. Malaysian policymakers must understand the symmetric and asymmetric effects of CC on RP and agricultural policies that will promote sustainable agricultural development and food security.

Towards Practical BCI-Driven Wheelchairs: A Systematic Review Study.

The use of brain signals in controlling wheelchairs is a promising solution for many disabled individuals, specifically those who are suffering from motor neuron disease affecting the proper functioning of their motor units. Almost two decades since the first work, the applicability of EEG-driven wheelchairs is still limited to laboratory environments. In this work, a systematic review study has been conducted to identify the state-of-the-art and the different models adopted in the literature. Furthermore, a strong emphasis is devoted to introducing the challenges impeding a broad use of the technology as well as the latest research trends in each of those areas.

Energy consumption, CO2 emissions, foreign direct investment, and economic growth in Malaysia: an NARDL technique.

This study seeks to ascertain whether there is an unbalanced link  between CO2 emissions, foreign direct investment, and economic growth in Malaysia over a 40-year timeframe between 1980 and 2019. We investigated the asymmetric relationship , using  non-linear autoregressive distributed lag (NARDL) technique. The findings showed a noteworthy asymmetry between FDI, CO2 emissions, and GDP in Malaysia. The long-term and short-term effects of negative FDI on GDP are both equivalent to 0.028 and 0.021, respectively. This suggests that, compared to short-term fluctuations, long-term negative FDI adjustments have a considerably more negative impact on economic growth. The coefficient of positive (CO2+) and negative (CO2-) changes in economic growth is equal to 0.086 and - 0.152, respectively. It indicates that positive changes in CO2 emissions have stronger effects in the long run than negative shocks. Considering an asymmetric association between these two variables in the short and long term, Malaysian policymakers must comprehend the dynamic relationship between FDI, CO2 emissions, and GDP to plan appropriate economic and environmental policies that will support sustainable economic development and ensure a safer environment.

Cyclone: an accessible pipeline to analyze, evaluate and optimize multiparametric cytometry data.

In the past decade, high-dimensional single cell technologies have revolutionized basic and translational immunology research and are now a key element of the toolbox used by scientists to study the immune system. However, analysis of the data generated by these approaches often requires clustering algorithms and dimensionality reduction representation which are computationally intense and difficult to evaluate and optimize. Here we present Cyclone, an analysis pipeline integrating dimensionality reduction, clustering, evaluation and optimization of clustering resolution, and downstream visualization tools facilitating the analysis of a wide range of cytometry data. We benchmarked and validated Cyclone on mass cytometry (CyTOF), full spectrum fluorescence-based cytometry, and multiplexed immunofluorescence (IF) in a variety of biological contexts, including infectious diseases and cancer. In each instance, Cyclone not only recapitulates gold standard immune cell identification, but also enables the unsupervised identification of lymphocytes and mononuclear phagocytes subsets that are associated with distinct biological features. Altogether, the Cyclone pipeline is a versatile and accessible pipeline for performing, optimizing, and evaluating clustering on variety of cytometry datasets which will further power immunology research and provide a scaffold for biological discovery.

Examining the role of road safety audits worldwide: exploring road safety expert's opinions.

Road safety audit (RSA) is a method used to proactively identify safety risks in road projects from planning, design, and construction stages. The effectiveness of the implementation of RSAs varies across the globe. This paper provides an understanding of road safety auditor's opinions and attitudes by using data collected from an online questionnaire filled by 408 road safety experts with varying demographic and technical backgrounds. Results demonstrated that majority of respondents agreed that RSA is an effective tool to improve road safety. Compared to high-income countries, respondents from low- and middle-income countries had less knowledge about RSA and less access to RSA guidelines. The results also indicate that many road safety auditors have a misunderstanding of the independence requirement for conducting RSA. The results of this paper can be used to inform and develop improved guidance to improve RSA generally and promote RSA as an effective road safety engineering tool.

Empowering human-AI teams via Intentional Behavioral Synchrony.

As Artificial Intelligence (AI) proliferates across various sectors such as healthcare, transportation, energy, and military applications, the collaboration between human-AI teams is becoming increasingly critical. Understanding the interrelationships between system elements - humans and AI - is vital to achieving the best outcomes within individual team members' capabilities. This is also crucial in designing better AI algorithms and finding favored scenarios for joint AI-human missions that capitalize on the unique capabilities of both elements. In this conceptual study, we introduce Intentional Behavioral Synchrony (IBS) as a synchronization mechanism between humans and AI to set up a trusting relationship without compromising mission goals. IBS aims to create a sense of similarity between AI decisions and human expectations, drawing on psychological concepts that can be integrated into AI algorithms. We also discuss the potential of using multimodal fusion to set up a feedback loop between the two partners. Our aim with this work is to start a research trend centered on exploring innovative ways of deploying synchrony between teams of non-human members. Our goal is to foster a better sense of collaboration and trust between humans and AI, resulting in more effective joint missions.

Role of deep brain stimulation (DBS) in addiction disorders.

Background: Addiction disorders pose significant challenges to public health, necessitating innovative treatments. This assesses deep brain stimulation (DBS) as a potential intervention for addiction disorders. Methods: A literature review was carried out with a focus on the role of DBS in addiction disorders and its future implications in neurosurgical research. Results: The online literature shows that DBS precisely modulates certain brain regions to restore addiction-related neural circuits and promote behavioral control. Conclusion: Preclinical evidence demonstrates DBS's potential to rebalance neural circuits associated with addiction, and early clinical trials provide encouraging outcomes in enhancing addiction-related outcomes. Ethical considerations, long-term safety, and personalized patient selection require further investigation.

Packing a Punch: Fight Bite Induced Septic Joint.

'Fight bites' constitute a considerable number of accidental human bite injuries. Where the mechanism involves a closed fist contacting another person's teeth, the subsequent injury tends to involve the metacarpophalangeal joint region. These injuries are unique for their seemingly benign appearance on initial presentation. Their presence can easily be missed if the treating physician does not seek investigative history and a high index of suspicion. If improperly managed, fight bites may be associated with the introduction of bacteria that may invade deeper tissues, causing potential debilitation from progressive infection. Our case discusses a 33-year-old female who presented three weeks after an altercation where a fight bite occurred but was not treated with antibiotics on discharge. Her clinical presentation matched a flexor sheath infection, which was revealed after investigation to be a consequence of a septic metacarpophalangeal joint that had also progressed to involve the underlying bones. The case outlines the dangers of improper assessment and management of fight bite injuries and reviews best practices surrounding the recognition, assessment, and treatment of these patients in the Emergency Department.

Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage.

Anti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of 2 IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitized mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion was rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provided only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protected against death after acute deletion of A20 and Abin-1 in IECs. A20- and Abin-1-deficient IECs were sensitized to TNF-independent, TNFR1-mediated death in response to lymphotoxin α (LTα) homotrimers. Blockade of LTα in vivo reduced weight loss and improved survival when combined with partial deletion of MyD88. Biopsies of inflamed colon mucosa from patients with IBD exhibited increased LTA and IL1B expression, including a subset of patients with active colitis on anti-TNF therapy. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.

Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

In vitro comparison of the accuracy (precision and trueness) of eight dental scanners for dental bridge scanning.

BACKGROUND: Dental scanners play a critical role in computer-aided design/computer-aided manufacturing technology. This study aimed to compare the accuracy (precision and trueness) of eight dental scanners for dental bridge scanning. MATERIALS AND METHODS: In this in-vitro experimental study, a typodont model with a missing maxillary right first molar was prepared for a 3-unit fixed partial denture. Each scanner (Sirona inEos inLab, Sirona X5, Dentium, Imes icore 350I I3D, Amann Girrbach map 100, 3Shape D100, 3Shape E3) performed seven scans of the typodont, and the data were analyzed using 3D-Tool software. The abutment length, abutment width, arch length, and interdental distance were measured. To assess the accuracy of each scanner, trueness was evaluated by superimposing the scanned data on true values obtained by the 3shape Triosscanner as the reference. Precision was evaluated by superimposing a pair of data sets obtained from the same scanner. Precision and trueness of the scanners were compared using the one-way ANOVA followed by the post-hoc Tukey's HSD test and one-sample t-test (P<0.05 was considerer significant). RESULTS: The precision of scanners ranged from 14 µm (3Shape Trios) to 45 µm (Imes icore 350i), whereas the trueness ranged from 38 µm (3Shape d700) to 71 µm (Sirona X5). CONCLUSION: The reported trueness values for 3Shape Trios, Sirona inEos inLab, Sirona x5, Dentium, Imes icore350i, Amann Girrbach, 3Shape d700, and 3Shape e3 were 63, 45, 71, 67, 70, 53, 38, and 42 µm, respectively, whereas the precision values were 14, 29, 44, 34, 45, 44, 30 and 28 µm, respectively.

Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer.

The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins - caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin - with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.

Acute-Hypoxemia-Induced Right-To-Left Shunting in the Presence of Patent Foramen Ovale.

Patent foramen ovale (PFO) is a common congenital abnormality of the heart. It results from incomplete closure of foramen ovale that persists in adulthood. Most individuals with PFO are asymptomatic and are discovered incidentally. The left atrial pressure is generally higher than the right atrial pressure, which prevents blood flow against the gradient; however, any medical condition that increases the pulmonary artery pressure can lead to reversal of blood flow from right to left by elevating right atrial pressure. We present a case of a 59-year-old female who presented with complaints of shortness of breath associated with bilateral lower-extremity edema and was found to have acute decompensated heart failure and atrial fibrillation. Transesophageal echocardiogram (TEE) with cardioversion was performed. Propofol was given for conscious sedation; however, the procedure was terminated as patient became hypoxemic and was noted to have moderately dilated right ventricle (RV) with hypokinesia and PFO with right-to-left shunting. It also demonstrated mild mitral regurgitation, mild left ventricular hypertrophy, and a left ventricular ejection fraction of 55-60%. In contrast to TEE findings, while the patient was having normal oxygen saturation, transthoracic echocardiogram showed left-to-right shunting instead of right-to-left and no RV hypokinesia was noted. In conclusion, this case draws attention to the relationship between acute hypoxemia and right-to-left shunting in a patient with PFO. This case illustrates and highlights the need for more prospective studies to establish a relationship between acute hypoxemia and right-to-left shunting in the presence of PFO.

The effect of intravenous tranexamic acid on preventing the progress of cerebral hemorrhage in patients with brain traumatic injuries compared to placebo: A randomized clinical trial.

Background: Head trauma is one of the common reasons for patient attendance in the emergency ward. This study investigated the effect of tranexamic acid as a cheap, easily available antifibrinolytic drug on reducing the progress of cerebral hemorrhage compared to placebo. Methods: This double-blind controlled clinical trial was performed on 120 traumatized patients presenting to the emergency room of Shahid Rahnemoon hospital during 2014-2015, Yazd, Iran. Those patients who met the inclusion criteria were randomly allocated into 2 groups. Group A received tranexamic acid, while group B received placebo parenterally. Finally, 56 patients in Group A and 44 in Group B were analyzed. The patients underwent brain CT scan and were followed up for ICU stay in days. Also, the number of patients who died during the first 7 days of hospitalization was recorded. The data were analyzed with SPSS20 using independent samples t test and chi-square test. Results: The mean age of the patients was 41±20.27 years. Also, 20 patients (20%) were female and 80 were male (80%). There was no significant difference between the drug group and placebo group in the rate of hemorrhage volume progress (p=0.824). Regarding patients' ICU stay, the ICU stay of the tranexamic acid group decreased significantly compared to the placebo group (p=0.001). No significant difference was found between the intervention group and placebo group in the mortality rate of patients during the first 7 days of hospitalization (p=0.236). Conclusion: Tranexamic acid has no effect on reducing cerebral hemorrhage volume in patients. Although this drug was not effective in reducing mortality rate in patients, it decreased their ICU stay.

Diagnostic Accuracy of Three Cone Beam Computed Tomography Systems and Periapical Radiography for Detection of Fenestration Around Dental Implants.

CONTEXT: Early detection of peri-implant bone defects is highly important to prevent further bone loss and implant failure. AIMS: This study aimed to assess the diagnostic accuracy of three cone-beam computed tomography (CBCT) systems and periapical radiography for detection of fenestration around dental implants. METHODS: Thirty-one titanium implants were placed in the bovine ribs, in which peri-implant fenestration were simulated. Using a round fissure bur, fenestration defects were created in the apical-third region of implants. CBCT and PA radiographs were obtained before and after creating the defects. The results were analyzed using Chi-square test; kappa coefficient; Cochran's Q-test; McNemar's test; and sensitivity, specificity, positive predictive value, and negative predictive value; and receiver operating characteristic curve. RESULTS: A significant agreement was noted between the two observers in the detection of defect-free samples in all imaging systems (P < 0.05). In detection of samples with defects, a significant agreement was observed between the two observers in use of Cranex three-dimensional and NewTom 3G systems (P < 0.05), but the agreement was not significant for detection of defects in use of Promax 3D (P > 0.05). The results showed no significant difference among the four imaging systems in detection of defect-free samples while the difference was significant among the four groups for detection of defects (P < 0.05). NewTom had the highest sensitivity (75.81%) and specificity (100%) for detection of fenestration. CONCLUSIONS: Within the limitations of CBCT systems different kVp used by different systems, artifacts and noises that influences image quality, difference in diagnostic value of different CBCT systems is due to the differences in type of detector and voxel size. In terms of the type of detector, our results showed that NewTom 3G, which has a higher (kVP) than other systems and the highest accuracy for detection of fenestration.

Label-free dynamic segmentation and morphological analysis of subcellular optical scatterers.

Imaging without fluorescent protein labels or dyes presents significant advantages for studying living cells without confounding staining artifacts and with minimal sample preparation. Here, we combine label-free optical scatter imaging with digital segmentation and processing to create dynamic subcellular masks, which highlight significantly scattering objects within the cells' cytoplasms. The technique is tested by quantifying organelle morphology and redistribution during cell injury induced by calcium overload. Objects within the subcellular mask are first analyzed individually. We show that the objects' aspect ratio and degree of orientation ("orientedness") decrease in response to calcium overload, while they remain unchanged in untreated control cells. These changes are concurrent with mitochondrial fission and rounding observed by fluorescence, and are consistent with our previously published data demonstrating scattering changes associated with mitochondrial rounding during calcium injury. In addition, we show that the magnitude of the textural features associated with the spatial distribution of the masked objects' orientedness values, changes by more than 30% in the calcium-treated cells compared with no change or changes of less than 10% in untreated controls, reflecting dynamic changes in the overall spatial distribution and arrangement of subcellular scatterers in response to injury. Taken together, our results suggest that our method successfully provides label-free morphological signatures associated with cellular injury. Thus, we propose that dynamically segmenting and analyzing the morphology and organizational patterns of subcellular scatterers as a function of time can be utilized to quantify changes in a given cellular condition or state.