Platelet releasates mitigate the endotheliopathy of trauma.

BACKGROUND: Platelets are well known for their roles in hemostasis, but they also play a key role in thromboinflammatory pathways by regulating endothelial health, stimulating angiogenesis, and mediating host defense through both contact dependent and independent signaling. When activated, platelets degranulate releasing multiple active substances. We hypothesized that the soluble environment formed by trauma platelet releasates attenuates thromboinflammation via mitigation of trauma induced endothelial permeability and metabolomic reprogramming. METHODS: Blood was collected from injured and healthy patients to generate platelet releasates and plasma in parallel. Permeability of endothelial cells when exposed to trauma platelet releasates (TPR) and plasma (TP) was assessed via resistance measurement by Electric Cell-substrate Impedance Sensing (ECIS). Endothelial cells treated with TPR and TP were subjected to mass spectrometry-based metabolomics. RESULTS: TP increased endothelial permeability, whereas TPR decreased endothelial permeability when compared to untreated cells. When TP and TPR were mixed ex vivo, TPR mitigated TP-induced permeability, with significant increase in AUC compared to TP alone. Metabolomics of TPR and TP demonstrated disrupted redox reactions and anti-inflammatory mechanisms. CONCLUSION: TPRs provide endothelial barrier protection against TP-induced endothelial permeability. Our findings highlight a potential beneficial action of activated platelets on the endothelium in injured patients through disrupted redox reactions and increased antioxidants. Our findings support that soluble signaling from platelet degranulation may mitigate the endotheliopathy of trauma. The clinical implications of this are that activated platelets may prove a promising therapeutic target in the complex integration of thrombosis, endotheliopathy, and inflammation in trauma. LEVEL OF EVIDENCE: Prognostic/Epidemiological, Level III.

Adapting an Intervention to Improve Acute Myocardial Infarction Care in Tanzania: Co-Design of the MIMIC Intervention.

Background: Uptake of evidence-based care for acute myocardial infarction (AMI) is suboptimal in Tanzania, but there are currently no published interventions to improve AMI care in sub-Saharan Africa. Objectives: Co-design a quality improvement intervention for AMI care tailored to local contextual factors. Methods: An interdisciplinary design team consisting of 20 physicians, nurses, implementation scientists, and administrators met from June 2022 through August 2023. Half of the design team consisted of representatives from the target audience, emergency department physicians and nurses at a referral hospital in northern Tanzania. The design team reviewed multiple published quality improvement interventions focusing on ED-based AMI care. After selecting a multicomponent intervention to improve AMI care in Brazil (BRIDGE-ACS), the design team used the ADAPT-ITT framework to adapt the intervention to the local context. Findings: The design team audited current AMI care processes at the study hospital and reviewed qualitative data regarding barriers to care. Multiple adaptations were made to the original BRIDGE-ACS intervention to suit the local context, including re-designing the physician reminder system and adding patient educational materials. Additional feedback was sought from topical experts, including patients with AMI. Draft intervention materials were iteratively refined in response to feedback from experts and the design team. The finalized intervention, Multicomponent Intervention to Improve Myocardial Infarction Care in Tanzania (MIMIC), consisted of five core components: physician reminders, pocket cards, champions, provider training, and patient education. Conclusion: MIMIC is the first locally tailored intervention to improve AMI care in sub-Saharan Africa. Future studies will evaluate implementation outcomes and efficacy.

The use of deep learning state-of-the-art architectures for oral epithelial dysplasia grading: A comparative appraisal.

BACKGROUND: Dysplasia grading systems for oral epithelial dysplasia are a source of disagreement among pathologists. Therefore, machine learning approaches are being developed to mitigate this issue. METHODS: This cross-sectional study included a cohort of 82 patients with oral potentially malignant disorders and correspondent 98 hematoxylin and eosin-stained whole slide images with biopsied-proven dysplasia. All whole-slide images were manually annotated based on the binary system for oral epithelial dysplasia. The annotated regions of interest were segmented and fragmented into small patches and non-randomly sampled into training/validation and test subsets. The training/validation data were color augmented, resulting in a total of 81,786 patches for training. The held-out independent test set enrolled a total of 4,486 patches. Seven state-of-the-art convolutional neural networks were trained, validated, and tested with the same dataset. RESULTS: The models presented a high learning rate, yet very low generalization potential. At the model development, VGG16 performed the best, but with massive overfitting. In the test set, VGG16 presented the best accuracy, sensitivity, specificity, and area under the curve (62%, 62%, 66%, and 65%, respectively), associated with the higher loss among all Convolutional Neural Networks (CNNs) tested. EfficientB0 has comparable metrics and the lowest loss among all convolutional neural networks, being a great candidate for further studies. CONCLUSION: The models were not able to generalize enough to be applied in real-life datasets due to an overlapping of features between the two classes (i.e., high risk and low risk of malignization).

Clinicians' perception of oral potentially malignant disorders: a pitfall for image annotation in supervised learning.

OBJECTIVE: The present study aims to quantify clinicians' perceptions of oral potentially malignant disorders (OPMDs) when evaluating, classifying, and manually annotating clinical images, as well as to understand the source of inter-observer variability when assessing these lesions. The hypothesis was that different interpretations could affect the quality of the annotations used to train a Supervised Learning model. STUDY DESIGN: Forty-six clinical images from 37 patients were reviewed, classified, and manually annotated at the pixel level by 3 labelers. We compared the inter-examiner assessment based on clinical criteria through the κ statistics (Fleiss's kappa). The segmentations were also compared using the mean pixel-wise intersection over union (IoU). RESULTS: The inter-observer agreement for homogeneous/non-homogeneous criteria was substantial (κ = 63, 95% CI: 0.47-0.80). For the subclassification of non-homogeneous lesions, the inter-observer agreement was moderate (κ = 43, 95% CI: 0.34-0.53) (P < .001). The mean IoU of 0.53 (±0.22) was considered low. CONCLUSION: The subjective clinical assessment (based on human visual observation, variable criteria that have suffered adjustments over the years, different educational backgrounds, and personal experience) may explain the source of inter-observer discordance for the classification and annotation of OPMD. Therefore, there is a strong probability of transferring the subjectivity of human analysis to artificial intelligence models. The use of large data sets and segmentation based on the union of all labelers' annotations holds the potential to overcome this limitation.

Machine learning for detection and classification of oral potentially malignant disorders: A conceptual review.

Oral potentially malignant disorders represent precursor lesions that may undergo malignant transformation to oral cancer. There are many known risk factors associated with the development of oral potentially malignant disorders, and contribute to the risk of malignant transformation. Although many advances have been reported to understand the biological behavior of oral potentially malignant disorders, their clinical features that indicate the characteristics of malignant transformation are not well established. Early diagnosis of malignancy is the most important factor to improve patients' prognosis. The integration of machine learning into routine diagnosis has recently emerged as an adjunct to aid clinical examination. Increased performances of artificial intelligence AI-assisted medical devices are claimed to exceed the human capability in the clinical detection of early cancer. Therefore, the aim of this narrative review is to introduce artificial intelligence terminology, concepts, and models currently used in oncology to familiarize oral medicine scientists with the language skills, best research practices, and knowledge for developing machine learning models applied to the clinical detection of oral potentially malignant disorders.

Over-the-Scope-Clips Can Be Fired Safely Over a Guidewire: Proof of Concept in an Ex-Vivo Porcine Model.

Background and Objectives: To assist in achieving optimal position when deploying over-the-scope (OTS)-clips, the concept of cannulating the defect with a guidewire, backloading the endoscope onto the wire, and firing the OTS-clip over the wire with subsequent wire removal has been demonstrated. The safety of this technique has not been evaluated. Methods: An ex-vivo porcine foregut model was utilized. Biopsy punches were used to create 3-mm diameter full-thickness gastrointestinal tract defects through which a guidewire was threaded. An endoscope was backloaded over the wire and OTS-clips (OVESCO, Tuebingen, Germany) were fired over the mucosal defect and wire. The wire was removed through the endoscope and the removal difficulty was graded using a Likert scale. This process was repeated for each unique combination of nine OTS-clip types, two wire types, four wire angles, and three tissue types. Statistical analysis included t test and ANOVA. Results: Two hundred sixteen OTS-clip firings with wire removal attempts were performed with the following Likert score breakdown: 1 - No difficulty (80.6%), 2 - mild difficulty (16.2%), 3 - moderate difficulty (2.3%), 4 - extreme difficulty (0.9%), and 5 - unable to remove (0%). Statistically significant differences were noted in removal difficulty between OTS-clip sizes (p < 0.05). No differences were identified between clip teeth types, wire types, tissue types, and wire angles (p > 0.05). Conclusion: In this ex-vivo model, the guidewire was successfully removed through the endoscope in all cases. This technique can be employed to facilitate OTS-clip closure of gastrointestinal tract defects, but further study is indicated before wide clinical implementation.

Machine learning concepts applied to oral pathology and oral medicine: A convolutional neural networks' approach.

INTRODUCTION: Artificial intelligence models and networks can learn and process dense information in a short time, leading to an efficient, objective, and accurate clinical and histopathological analysis, which can be useful to improve treatment modalities and prognostic outcomes. This paper targets oral pathologists, oral medicinists, and head and neck surgeons to provide them with a theoretical and conceptual foundation of artificial intelligence-based diagnostic approaches, with a special focus on convolutional neural networks, the state-of-the-art in artificial intelligence and deep learning. METHODS: The authors conducted a literature review, and the convolutional neural network's conceptual foundations and functionality were illustrated based on a unique interdisciplinary point of view. CONCLUSION: The development of artificial intelligence-based models and computer vision methods for pattern recognition in clinical and histopathological image analysis of head and neck cancer has the potential to aid diagnosis and prognostic prediction.

Esophagogastric Junction Outflow Obstruction and Hiatal Hernia: Is Hernia Repair Alone Sufficient?

Introduction: Esophagogastric junction outflow obstruction (EGJOO) is attributed to primary/idiopathic causes or secondary/mechanical causes, including hiatal hernias (HH). While patients with HH and EGJOO (HH+EGJOO) may undergo HH repair without myotomy, it is unclear if an underlying motility disorder is missed by therapy which addresses only the secondary EGJOO cause. The goal of this study was to determine if HH repair alone is sufficient management for HH+EGJOO patients. Methods: A retrospective review of patients who underwent HH repair between January 1, 2016 and January 31, 2020 was performed. Patients who underwent high-resolution esophageal manometry(HREM) within one year before HH repair were included. Patients with and without EGJOO on pre-operative HREM were compared. Results: Sixty-three patients were identified. Pre-operative HREM findings included: 43 (68.3%) normal, 13 (20.6%) EGJOO, 4 (6.3%) minor disorder or peristalsis, 2 (3.2%) achalasia, and 1 (1.6%) major disorder of peristalsis. No differences between patients with EGJOO or normal findings on pre-operative manometry were found in pre-operative demographics/risk factors, pre-operative symptoms, and pre-operative HREM, except higher integrated relaxation pressure in EGJOO patients. No differences were noted in length of stay, 30-day complications, long-term persistent symptoms, or recurrence with mean follow-up of 26-months. Of the 3 (23.1%) EGJOO patients with persistent symptoms, 2 underwent HREM demonstrating persistent EGJOO and none required endoscopic/surgical myotomy. Conclusion: Most HH+EGJOO patients experienced symptom resolution following HH repair alone and none required additional intervention to address a missed primary motility disorder. Further study is required to determine optimal management of patients with persistent EGJOO following HH repair.

Gene regulatory networks shape developmental plasticity of root cell types under water extremes in rice.

Understanding how roots modulate development under varied irrigation or rainfall is crucial for development of climate-resilient crops. We established a toolbox of tagged rice lines to profile translating mRNAs and chromatin accessibility within specific cell populations. We used these to study roots in a range of environments: plates in the lab, controlled greenhouse stress and recovery conditions, and outdoors in a paddy. Integration of chromatin and mRNA data resolves regulatory networks of the following: cycle genes in proliferating cells that attenuate DNA synthesis under submergence; genes involved in auxin signaling, the circadian clock, and small RNA regulation in ground tissue; and suberin biosynthesis, iron transporters, and nitrogen assimilation in endodermal/exodermal cells modulated with water availability. By applying a systems approach, we identify known and candidate driver transcription factors of water-deficit responses and xylem development plasticity. Collectively, this resource will facilitate genetic improvements in root systems for optimal climate resilience.

Complications and outcomes of posterior fossa decompression with duraplasty versus without duraplasty for pediatric patients with Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: The aim of this study was to determine differences in complications and outcomes between posterior fossa decompression with duraplasty (PFDD) and without duraplasty (PFD) for the treatment of pediatric Chiari malformation type I (CM1) and syringomyelia (SM). METHODS: The authors used retrospective and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM1-SM who received PFD or PFDD and had at least 1 year of follow-up data. Preoperative, treatment, and postoperative characteristics were recorded and compared between groups. RESULTS: A total of 692 patients met the inclusion criteria for this database study. PFD was performed in 117 (16.9%) and PFDD in 575 (83.1%) patients. The mean age at surgery was 9.86 years, and the mean follow-up time was 2.73 years. There were no significant differences in presenting signs or symptoms between groups, although the preoperative syrinx size was smaller in the PFD group. The PFD group had a shorter mean operating room time (p < 0.0001), fewer patients with > 50 mL of blood loss (p = 0.04), and shorter hospital stays (p = 0.0001). There were 4 intraoperative complications, all within the PFDD group (0.7%, p > 0.99). Patients undergoing PFDD had a 6-month complication rate of 24.3%, compared with 13.7% in the PFD group (p = 0.01). There were no differences between groups for postoperative complications beyond 6 months (p = 0.33). PFD patients were more likely to require revision surgery (17.9% vs 8.3%, p = 0.002). PFDD was associated with greater improvements in headaches (89.6% vs 80.8%, p = 0.04) and back pain (86.5% vs 59.1%, p = 0.01). There were no differences between groups for improvement in neurological examination findings. PFDD was associated with greater reduction in anteroposterior syrinx size (43.7% vs 26.9%, p = 0.0001) and syrinx length (18.9% vs 5.6%, p = 0.04) compared with PFD. CONCLUSIONS: PFD was associated with reduced operative time and blood loss, shorter hospital stays, and fewer postoperative complications within 6 months. However, PFDD was associated with better symptom improvement and reduction in syrinx size and lower rates of revision decompression. The two surgeries have low intraoperative complication rates and comparable complication rates beyond 6 months.

Direct Oral Anticoagulants for the Treatment of Cancer-Associated Venous Thromboembolism: A Latin American Perspective.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct oral anticoagulants (DOACs) are now recommended for the treatment of cancer-associated VTE. The decision to use a DOAC requires consideration of bleeding risk, particularly in patients with gastrointestinal (GI) malignancies, the cost-benefit and convenience of oral therapy, and patient preference. While efficacy with apixaban, edoxaban, and rivaroxaban versus dalteparin has been consistent in the treatment of cancer-associated VTE, heterogeneity is evident with respect to major GI bleeding, with an increased risk with edoxaban and rivaroxaban but not apixaban. Although cost and accessibility vary in different countries of Latin America, DOACs should be considered for the long-term treatment of cancer-associated VTE in all patients who are likely to benefit. Apixaban may be the preferred DOAC in patients with GI malignancies and LMWH may be preferred for patients with upper or unresected lower GI tumors. Vitamin K antagonists should only be used for anticoagulation when DOACs and low molecular weight heparin are inaccessible or unsuitable.

An Exceedingly Rare Case of Antithrombin III Deficiency and Catastrophic Antiphospholipid-Like Disease.

Antithrombin III (AT III) is a critical component of the coagulation cascade that functions primarily to inhibit activated coagulation factors IIa and Xa. AT III deficiency is a disorder that predisposes patients to thromboemboli. Antiphospholipid syndrome (APS) is an autoimmune disorder that predisposes patients to vascular and microvascular thrombosis, which can often be devastating and lead to multiorgan involvement. The mainstay of treatment for both conditions involves the use of lifetime vitamin K antagonists. Recent studies suggest that patients with APS refractory to warfarin therapy may benefit from the addition of aspirin, statin, or hydroxychloroquine; low weight molecular heparin; or a combination regimen. Studies have also suggested that patients with AT III deficiency refractory to warfarin therapy may see improvement with use of a novel oral anticoagulant. This case report describes the recurrent hospitalizations of a 45-year-old patient who presented with multiorgan thrombosis involving the descending aorta, deep lower extremity veins, superior mesenteric artery and artery of the brain. This led to mesenteric ischemia, limb necrosis and a subacute frontal cortex infarct. Initial anticoagulation therapy was refractory to the use of warfarin. Enoxaparin therapy was initiated, resulting in no further thrombotic events. Clinicians should consider poor gastrointestinal absorption of warfarin in patients who fail to reach therapeutic anticoagulation goals. In addition, a thorough workup for hereditary and acquired thrombophilias should be performed in patients who present with recurrent thromboemboli, as these disorders increase the risk of poor patient outcomes if left untreated.

Patient's satisfaction with facial appearance and psycho-social wellness after orthognathic surgery among Hong Kong Chinese using the FACE-Q.

PURPOSE: To assess and compare the changes in satisfaction with facial appearance and psycho-social well-being in dento-skeletal class II and III patients after orthognathic surgery with the FACE-Q among Hong Kong Chinese. METHODS: The questionnaires for thirteen orthognathic-relevant FACE-Q scales, translated into Cantonese and validated, were administered to Hong Kong Chinese patients before and after orthognathic surgery in the short- and long-term, respectively. The assessed scales were categorized into four main domains: satisfaction with facial appearance, quality of life, patient's experience of care, and adverse effects. RESULTS: Generally, highly significant (p < 0.001) improved FACE-Q scores were found in the long-term in the scales investigating the satisfaction with overall facial appearance, lower face and jawline, and chin. Although dento-skeletal class III patients demonstrated significantly improved satisfaction with their post-surgical nostril appearance (p = 0.003), this was not evident in dento-skeletal class II patients (p = 0.231). Nonetheless, both class II and class III subjects have also revealed significantly improved psychological well-being (0.003; <0.001) and social function (0.001; <0.001) in the long-term. Age was not found to be correlated with all scales for satisfaction of facial appearance. CONCLUSION: Previously validated Face-Q scales are valuable instruments to measure clinical outcomes, psychological well-being and social function in Cantonese speaking patients. Both Class II and Class III patients showed significantly improved satisfaction with facial appearance, psychological well-being and social function after orthognathic surgery regardless of skeletal pattern and gender, confirming findings in other ethnicities.

Treating Center Volume and Congenital Diaphragmatic Hernia Outcomes in California.

OBJECTIVE: To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators. STUDY DESIGN: A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes. RESULTS: There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n = 206), and 19.8% (n = 107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P = .003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P = .03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P = .06). CONCLUSIONS: Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.

Quaternary climate changes as speciation drivers in the Amazon floodplains.

The role of climate as a speciation driver in the Amazon has long been discussed. Phylogeographic studies have failed to recover synchronous demographic responses across taxa, although recent evidence supports the interaction between rivers and climate in promoting speciation. Most studies, however, are biased toward upland forest organisms, while other habitats are poorly explored and could hold valuable information about major historical processes. We conducted a comparative phylogenomic analysis of floodplain forest birds to explore the effects of historical environmental changes and current connectivity on population differentiation. Our findings support a similar demographic history among species complexes, indicating that the central portion of the Amazon River basin is a suture zone for taxa isolated across the main Amazonian sub-basins. Our results also suggest that changes in the fluvial landscape induced by climate variation during the Mid- and Late Pleistocene drove population isolation, leading to diversification with subsequent secondary contact.

Increased temperatures reduce the vectorial capacity of Aedes mosquitoes for Zika virus.

Rapid and significant range expansion of both Zika virus (ZIKV) and its Aedes vector species has resulted in ZIKV being declared a global health threat. Mean temperatures are projected to increase globally, likely resulting in alterations of the transmission potential of mosquito-borne pathogens. To understand the effect of diurnal temperature range on the vectorial capacity of Ae. aegypti and Ae. albopictus for ZIKV, longevity, blood-feeding and vector competence were assessed at two temperature regimes following feeding on infectious blood meals. Higher temperatures resulted in decreased longevity of Ae. aegypti [Log-rank test, χ2, df 35.66, 5, P < 0.001] and a decrease in blood-feeding rates of Ae. albopictus [Fisher's exact test, P < 0.001]. Temperature had a population and species-specific impact on ZIKV infection rates. Overall, Ae. albopictus reared at the lowest temperature regime demonstrated the highest vectorial capacity (0.53) and the highest transmission efficiency (57%). Increased temperature decreased vectorial capacity across groups yet more significant effects were measured with Ae. aegypti relative to Ae. albopictus. The results of this study suggest that future increases in temperature in the Americas could significantly impact vector competence, blood-feeding and longevity, and potentially decrease the overall vectorial capacity of Aedes mosquitoes in the Americas.

Introduction, Spread, and Establishment of West Nile Virus in the Americas.

The introduction of West Nile virus (WNV) to North America in 1999 and its subsequent rapid spread across the Americas demonstrated the potential impact of arboviral introductions to new regions, and this was reinforced by the subsequent introductions of chikungunya and Zika viruses. Extensive studies of host-pathogen-vector-environment interactions over the past two decades have illuminated many aspects of the ecology and evolution of WNV and other arboviruses, including the potential for pathogen adaptation to hosts and vectors, the influence of climate, land use and host immunity on transmission ecology, and the difficulty in preventing the establishment of a zoonotic pathogen with abundant wildlife reservoirs. Here, we focus on outstanding questions concerning the introduction, spread, and establishment of WNV in the Americas, and what it can teach us about the future of arboviral introductions. Key gaps in our knowledge include the following: viral adaptation and coevolution of hosts, vectors and the virus; the mechanisms and species involved in the large-scale spatial spread of WNV; how weather modulates WNV transmission; the drivers of large-scale variation in enzootic transmission; the ecology of WNV transmission in Latin America; and the relative roles of each component of host-virus-vector interactions in spatial and temporal variation in WNV transmission. Integrative studies that examine multiple factors and mechanisms simultaneously are needed to advance our knowledge of mechanisms driving transmission.

Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs.

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15-CD14+HLA-DR-/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.