Interpreting single-cell messages in normal and aberrant hematopoiesis with the Cell Marker Accordion.

Single-cell technologies offer a unique opportunity to explore cellular heterogeneity in hematopoiesis, reveal malignant hematopoietic cells with clinically significant features and measure gene signatures linked to pathological pathways. However, reliable identification of cell types is a crucial bottleneck in single-cell analysis. Available databases contain dissimilar nomenclature and non-concurrent marker sets, leading to inconsistent annotations and poor interpretability. Furthermore, current tools focus mostly on physiological cell types, lacking extensive applicability in disease. We developed the Cell Marker Accordion, a user-friendly platform for the automatic annotation and biological interpretation of single-cell populations based on consistency weighted markers. We validated our approach on peripheral blood and bone marrow single-cell datasets, using surface markers and expert-based annotation as the ground truth. In all cases, we significantly improved the accuracy in identifying cell types with respect to any single source database. Moreover, the Cell Marker Accordion can identify disease-critical cells and pathological processes, extracting potential biomarkers in a wide variety of contexts in human and murine single-cell datasets. It characterizes leukemia stem cell subtypes, including therapy-resistant cells in acute myeloid leukemia patients; it identifies malignant plasma cells in multiple myeloma samples; it dissects cell type alterations in splicing factor-mutant cells from myelodysplastic syndrome patients; it discovers activation of innate immunity pathways in bone marrow from mice treated with METTL3 inhibitors. The breadth of these applications elevates the Cell Marker Accordion as a flexible, faithful and standardized tool to annotate and interpret hematopoietic populations in single-cell datasets focused on the study of hematopoietic development and disease.

Can NIRS be a surrogate indicator of elective shunt in carotid endarterectomy? A single-center observational retrospective study says no.

BACKGROUND: Neuromonitoring during carotid endarterectomy (CEA) under general anesthesia is desirable and may be useful for preventing brain ischemia, but the selection of the most appropriate method remains controversial. PURPOSE: To determine the effectiveness of near infrared spectroscopy (NIRS) compared to multimodality intraoperative neuromonitoring (IONM) in indicating elective shunts and predicting postoperative neurological status. METHODS: This is a retrospective observational study including 86 consecutive patients with CEA under general anesthesia. NIRS and multimodality IONM were performed during the procedure. IONM included electroencephalography (EEG), somatosensory evoked potentials (SSEPs) and transcranial motor-evoked potentials (TcMEPs). Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated for each neuromonitoring modality. RESULTS: NIRS presented a sensitivity and a specificity for detecting brain ischemia of 77.7% and 89.6%, respectively (PPV = 46.6% and NPV = 97.2%). In contrast, a 100% sensitivity and specificity for multimodality IONM was determined (PPV and NPV = 100%). No significant difference (in demographical or clinical data) between "true positive" and "false-positive" patients was identified. Among the methods included in multimodality IONM, EEG showed the best results for predicting postoperative outcome after CEA (PPV and NPV=100%). CONCLUSION: NIRS is inferior to multimodality IONM in detecting brain ischemia and predicting postoperative neurological status during CEA under general anesthesia.

Structure and function of the TPR-domain immunophilins FKBP51 and FKBP52 in normal physiology and disease.

Coordinated cochaperone interactions with Hsp90 and associated client proteins are crucial for a multitude of signaling pathways in normal physiology, as well as in disease settings. Research on the molecular mechanisms regulated by the Hsp90 multiprotein complexes has demonstrated increasingly diverse roles for cochaperones throughout Hsp90-regulated signaling pathways. Thus, the Hsp90-associated cochaperones have emerged as attractive therapeutic targets in a wide variety of disease settings. The tetratricopeptide repeat (TPR)-domain immunophilins FKBP51 and FKBP52 are of special interest among the Hsp90-associated cochaperones given their Hsp90 client protein specificity, ubiquitous expression across tissues, and their increasingly important roles in neuronal signaling, intracellular calcium release, peptide bond isomerization, viral replication, steroid hormone receptor function, and cell proliferation to name a few. This review summarizes the current knowledge of the structure and molecular functions of TPR-domain immunophilins FKBP51 and FKBP52, recent findings implicating these immunophilins in disease, and the therapeutic potential of targeting FKBP51 and FKBP52 for the treatment of disease.

CT-based pathological lung opacities volume as a predictor of critical illness and inflammatory response severity in patients with COVID-19.

Objective: The aim of the study was to assess the impact of CT-based lung pathological opacities volume on critical illness and inflammatory response severity of patients with COVID-19. Methods: A retrospective, single center, single arm study was performed over a 30-day period. In total, 138 patients (85.2%) met inclusion criteria. All patients were evaluated with non-contrast enhanced chest CT scan at hospital admission. CT-based lung segmentation was performed to calculate pathological lung opacities volume (LOV). At baseline, complete blood count (CBC) and inflammation response biomarkers were obtained. The primary endpoint of the study was the occurrence of critical illness, as defined as, the need of mechanical ventilation and/or ICU admission. Mann-Whitney U test was performed for univariate analysis. Logistic regression analysis was performed to determine independent predictors of critical illness. Spearman analysis was performed to assess the correlation between inflammatory response biomarkers serum concentrations and LOV. Results: Median LOV was 28.64% (interquartile range [IQR], 6.33-47.22%). Correlation analysis demonstrated that LOV was correlated with higher levels of D-dimer (r = 0.51, p < 0.01), procalcitonin (r = 0.47, p < 0.01) and IL6 (r = 0.48, p < 0.01). Critical illness occurred in 51 patients (37%). Univariate analysis demonstrated that inflammatory response biomarkers and LOV were associated with critical illness (p < 0.05). However, multivariate analysis demonstrated that only D-dimer and LOV were independent predictors of critical illness. Furthermore, a ROC analysis demonstrated that a LOV equal or greater than 60% had a sensitivity of 82.1% and specificity of 70.2% to determine critical illness with an odds ratio of 19.4 (95% CI, 4.2-88.9). Conclusion: Critical illness may occur in up to 37% of the patients with COVID-19. Among patients with critical illness, higher levels of inflammatory response biomarkers with larger LOVs were observed. Furthermore, multivariate analysis demonstrated that pathological lung opacities volume was an independent predictor of critical illness. In fact, patients with a pathological lung opacities volume equal or greater than 60% had 19.4-fold increased risk of critical illness.

Cardiovascular risk factors and comorbidities in people living with HIV: A cross-sectional multicenter study from Colombia comorbidities in a Colombian PLWHIV population.

INTRODUCTION: HIV is an independent risk factor for cardiovascular diseases (CVD). There is insufficient information regarding comorbidities and cardiovascular risk factors in the Colombian HIV population. The aim of this study is to describe the prevalence of cardiovascular risk factors and comorbidities in patients from the HIV Colombian Group VIHCOL. METHODS: This is a multicenter, cross-sectional study conducted in the VIHCOL network in Colombia. Patients 18 years or older who had at least 6 months of follow-up were included. A stratified random sampling was performed to estimate the adjusted prevalence of cardiovascular risk factors and comorbidities. RESULTS: A total of 1616 patients were included. 83.2% were men, and the median age was 34 years. The adjusted prevalence for dyslipidemia, active tobacco use, hypothyroidism, and arterial hypertension was 51.2% (99% CI: 48.0%-54.4%), 7.6% (99% CI: 5.9%-9.3%), 7.4% (99% CI: 5.7%-9.1%), and 6.3% (99% CI: 4.8%-7.9%), respectively. CONCLUSIONS: In this Colombian HIV cohort, there is a high prevalence of modifiable CVD risk factors such as dyslipidemia and active smoking. Non-pharmacological and pharmacological measures for the prevention and management of these risk factors should be reinforced.

Computed Tomography-based Lung Residual Volume and Mortality of Patients With Coronavirus Disease-19 (COVID-19).

RATIONALE AND OBJECTIVES: To assess the effect of computed tomography (CT)-based residual lung volume (RLV) on mortality of patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: A single-center, retrospective study of a prospectively maintained database was performed. In total, 138 patients with COVID-19 were enrolled. Baseline chest CT scan was performed in all patients. CT-based automated and semi-automated lung segmentation was performed using the Alma Medical workstation to calculate normal lung volume, lung opacities volume, total lung volume, and RLV. The primary end point of the study was mortality. Univariate and multivariate analyses were performed to determine independent predictors of mortality. RESULTS: Overall, 84 men (61%) and 54 women (39%) with a mean age of 47.3 years (±14.3 y) were included in the study. Overall mortality rate was 21% (29 patients) at a median time of 7 days (interquartile range, 4 to 11 d). Univariate analysis demonstrated that age, hypertension, and diabetes were associated with death (P<0.01). Similarly, patients who died had lower normal lung volume and RLV than patients who survived (P<0.01). Multivariate analysis demonstrated that low RLV was the only independent predictor of death (odds ratio, 1.042; 95% confidence interval, 10.2-10.65). Furthermore, receiver operating characteristic curve analysis demonstrated that a RLV ≤64% significantly increased the risk of death (odds ratio, 4.8; 95% confidence interval, 1.9-11.7). CONCLUSION: Overall mortality of patients with COVID-19 may reach 21%. Univariate and multivariate analyses demonstrated that reduced RLV was the principal independent predictor of death. Furthermore, RLV ≤64% is associated with a 4-fold increase on the risk of death.

Anaesthesia and multimodality intraoperative neuromonitoring in carotid endarterectomy. Chronological evolution and effects on intraoperative neurophysiology.

Contingency data was retrospectively collected to evaluate the historical and current ability to provide multimodality intraoperative neurophysiological monitoring during carotid endarterectomy under two conditions: total intravenous anaesthesia (TIVA) and low dose halogenated anaesthesia (SEVO). 229 patients were monitored during carotid endarterectomy procedures under general anaesthesia between 2012 and 2020. 121 Patients were monitored with SEVO at a minimum alveolar concentration less than 0.7 and 108 were monitored using TIVA, according to common anaesthetic practice standards in our hospital across the years. Multimodality IONM was established with electroencephalography, somatosensory evoked potentials and motor evoked potentials. As compared to TIVA, patients monitored with SEVO showed significantly higher motor evoked potential thresholds (313.52 ± 77.74 SEVO and 218.93 V ± 103.2 V TIVA p < 0.05) and lower reproducibility. Electroencephalography and somatosensory evoked potentials showed no significant differences among the groups. When using SEVO, multimodality intraoperative neurophysiological monitoring during carotid endarterectomy could mask or miss a motor isolated change in patients in spite of low dose minimum alveolar concentration and of apparently adequate electroencephalography and somatosensory evoked potentials for monitoring. Given these difficulties, we believe the chronological transfer to TIVA could have improved our ability to establish multimodality intraoperative neurophysiological monitoring during carotid endarterectomy in recent times.

CT-Based Hepatic Residual Volume and Predictors of Outcomes of Patients with Hepatocellular Carcinoma Unsuitable for Surgical Therapy Undergoing Transarterial Chemoembolization.

RATIONALE AND OBJECTIVES: To assess the association between baseline CT-based volumetric parameters and biochemical hepatic evaluations, such as, Child-Pugh, MELD score, and modified MELD-Na score, on the prediction of outcomes of patients with HCC undergoing transarterial chemoembolization (TACE). MATERIALS AND METHODS: A retrospective of a prospectively maintained database, single arm, and single center study was performed including 41 patients with diagnosis of hepatocellular carcinoma treated with TACE. Study endpoints included liver dysfunction (new events of ascites, encephalopathy, and/or death) and overall survival rate. Multi-phase CT-based volumetric analysis was performed to calculate total liver volume and tumor volume using portal and late arterial phases, respectively. Residual volume was calculated subtracting the tumor volume minus the total liver volume. Child-Pugh, MELD score, and MELD-Na score were measured during the baseline evaluation. RESULTS: At a median follow-up time of 8 months (IQR, 5-14), 16 patients (39%) were diagnosed with hepatic dysfunction. In patients with hepatic dysfunction, the median residual hepatic volume was 1002.1 cc (IQR, 633-1077.1 cc) compared to patients with normal liver function post-TACE with a median residual volume of 1233 cc (IQR, 1018.7-1437.6 cc) (p = 0.02). Survival analysis demonstrated an overall survival rate of 95%, 90%, 85% at 30 days, 12 months, and 24 months, respectively. The overall survival rate in patients with Child-Pugh A was 100%, 97%, and 97% at 6, 12, and 24 months, respectively; compared to patients with Child Pugh B with an overall survival of rate of 86%, 78%, and 78% at 6, 12, and 24 months, respectively (p = 0.07). Median baseline MELD-Na score was higher in patients that died during the study period compared to patients that survived (6.7 [IQR, 5-14.2] versus 4.1 [IQR, 2.14-6.85]) (p = 0.09). CONCLUSION: Low baseline CT-based residual volume is associated with the occurrence of hepatic dysfunction at a median time of 8 months. Baseline Child-Pugh A patients were found to have higher survival rate than Child-Pugh B. Interestingly, higher baseline MELD-Na score was associated with mortality.

Medical Encounters During the United States Army Special Forces Assessment and Selection Course.

INTRODUCTION: The Special Forces Assessment and Selection (SFAS) is an extremely physically and mentally demanding 19- to 20-day course designed to determine whether Soldiers are qualified to enter the Special Forces Qualification Course. As a first step to understand medical problems during SFAS, this study examined injuries, illnesses, and activities associated with injuries during the course. MATERIALS AND METHODS: Medical events during the SFAS course were compiled from Sick Call Trackers (a log of medical encounters maintained by medical personnel in the field) and Chronology of Medical Care (Standard Form 600). Descriptive statistics were calculated for each injury and illness and injuries were compiled by the activities performed when the injuries occurred. RESULTS: Of the 800 Soldiers who volunteered for the study, 38% (n = 307/800) and 12% (n = 97/800) experienced one or more injuries and/or illnesses, respectively. The most common injuries were blisters and abrasions/lacerations with incidences of 20% (n = 158/800) and 13% (104/800), respectively. The most common illnesses were respiratory infections, other infections, contact dermatitis, and allergies with incidences of 7% (n = 57/800), 2% (n = 14/800), 2% (n = 14/800), and 2% (n = 13/800), respectively. Among all injuries recorded (n = 573), the most common were blisters (46%), abrasions/lacerations (24%), pain (not otherwise specified) (19%), tendonitis (3%), and sprains (3%). Among all illnesses recorded (n = 133), the most common were respiratory infections (56%), allergies (11%), contact dermatitis (11%), and other infections (11%). Most injuries were experienced during land navigation (44%), team events (20%), and foot marching (11%), running (6%), and the obstacle course (5%), but when the estimated time involved for each event was considered, activities with the highest injury rates were the obstacle course (65 injuries/hr), running (27 injuries/hr), the Combat Readiness Assessment (activity involving combat-related tasks) (20 injuries/hr), and foot marching (16 injuries/hr). CONCLUSION: The major limitations of this investigation were: 1) the low specificity with regard to many of the diagnoses/complaints; and 2) the fact that the medical problems reported here are only those seen by medical care providers and are likely an underestimate of the total morbidity in the SFAS course. Soldiers often self-treat and some may be reluctant to see medical personnel because of how it might affect their rating in the course. Nonetheless, this investigation alerts medical personnel to the injuries and illnesses to expect, and public health workers and leadership with activities to target for injury prevention measures during SFAS.

Data of the effects of acetone fraction from Sechium edule (Jacq.) S.w. edible roots in the kidney of endothelial dysfunction induced mice.

Endothelial dysfunction induced by Angiotensin II (AG II) plays an important role in the pathogenesis of hypertension and is accompanied by a prooxidative condition, which in turn induces an inflammatory state, vascular remodeling, and tissue damage including the kidney (Schmitt and Dirsch, 2009) [1]. New drugs that can control several of these pathologies are required. Sechium edule has been reported to possess antioxidant, anti-inflammatory and antihypertensive activity (Ibarra-Alvarado et al., 2010) [2]. This paper contains data complementary to those published in Journal of Ethnopharmacology (Moreno et al., 2018) [3], evaluating the effect in kidney of hypertensive mice of the acetone fraction from S. edule to control de pro-oxidative state, reduction of the inflammatory adhesion molecule (ICAM) and recruitment of inflammatory cells.

Acetone fraction from Sechium edule (Jacq.) S.w. edible roots exhibits anti-endothelial dysfunction activity.

ETHNOPHARMACOLOGICAL RELEVANCE: A recent ethnomedical survey on medicinal plants grown in Mexico revealed that Sechium edule (Jacq.) Sw. (Cucurbitaceae) is one of the most valued plant species to treat cardiovascular diseases, including hypertension. Fruits, young leaves, buds, stems, and tuberous roots of the plant are edible. Considering that endothelial dysfunction induced by Angiotensin II plays an important role in the pathogenesis of hypertension and is accompanied by a prooxidative condition, which in turn induces an inflammatory state, vascular remodeling, and tissue damage, and that S. edule has been reported to possess antioxidant, anti-inflammatory and antihypertensive activity, its capability to control endothelial dysfunction was also assessed. AIM OF THE STUDY: To assess in vivo the anti-endothelial dysfunction activity of the acetone fraction (rSe-ACE) of the hydroalcoholic extract from S. edule roots. MATERIALS AND METHODS: Endothelial dysfunction was induced in female C57BL/6 J mice by a daily intraperitoneal injection of angiotensin II for 10 weeks. Either rSe-ACE or losartan (as a control) were co-administered with angiotensin II for the same period. Blood pressure was measured at weeks 0, 5, and 10. Kidney extracts were prepared to determine IL1ß, IL4, IL6, IL10, IL17, IFNγ, TNFα, and TGFß levels by ELISA, along with the prooxidative status as assessed by the activity of antioxidant enzymes. The expression of ICAM-1 was evaluated by immunohistochemistry in kidney histological sections. Kidney and hepatic damage, as well as vascular tissue remodeling, were studied. RESULTS: The rSe-ACE fraction administered at a dose of 10 mg/kg was able to control hypertension, as well as the prooxidative and proinflammatory status in kidney as efficiently as losartan, returning mice to normotensive levels. Additionally, the fraction was more efficient than losartan to prevent liver and kidney damage. Phytochemical characterization identified cinnamic acid as a major compound, and linoleic, palmitic, and myristic acids as the most abundant non-polar components in the mixture, previously reported to aid in the control of hypertension, inflammation, and oxidative stress, three important components of endothelial dysfunction. IN CONCLUSION: this study demonstrated that rSe-ACE has anti-endothelial dysfunction activity in an experimental model and highlights the role of cinnamic acid and fatty acids in the observed effects.

Evidence of Protaphorura fimata (Collembola: Poduromorpha: Onychiuridae) feeding on germinating lettuce in the Salinas Valley of California.

A series of experiments were conducted to determine the impact of Protaphorura fimata Gisin (Family: Onychiuridae) feeding on seeds and germinating seedlings of lettuce, Lactuca sativa L. (Asteraceae). First, various densities of P. fimata were incubated with 25 lettuce seeds for 7 d and feeding injury was evaluated in three soilless arena experiments. As a second step, 100 P. fimata were incubated with 25 lettuce seeds in three arena experiments with soil media. Finally, in a commercial field the incidence and impact of P. fimata on recently planted lettuce was assessed following applications of pyrethroid-insecticides: 2 d before planting, at planting, and 20 d later. In experiments without soil, the number of ungerminated seeds, feeding injury sites, and plants with injury were significantly greater in arenas with P. fimata than without. Similarly, the number of germinated seedlings, shoot fresh, and dry weights, and the length and width of fully opened-leaves were greater in arenas without than with P. fimata in assays with soil. In the field, P. fimata densities were significantly lower in beds that received insecticides at 2 d before and at planting than in untreated beds. Also, the fresh and dry weights of lettuce plants were significantly greater in the beds that received insecticide than in untreated. The results clearly show that P. fimata is a pest of lettuce and can cause severe feeding injury to germinating seeds or seedlings, thereby reducing their growth rate. The potential implications of P. fimata feeding and feeding injury characteristics are discussed.