Plasma Ascorbic Acid Levels in Critically Ill Pediatric Patients.

Ascorbic acid, or vitamin C, is a physiological antioxidant that has been found to be deficient in critically ill adults with sepsis and acute respiratory distress system. In adults, ascorbic acid supplementation has been shown to reduce the need for vasopressors and mechanical ventilation. This study aimed to describe the prevalence of ascorbic acid deficiency in critically ill pediatric patients. This prospective, single-centered study analyzed 34 patients aged 1 month to 18 years old with septic shock and/or acute respiratory failure requiring mechanical ventilation in a quaternary, urban, pediatric intensive care unit. Plasma ascorbic acid levels were measured by high-performance liquid chromatography within 24 hours of meeting eligibility criteria. The median level was 23.34 µM (IQR [11.45, 39.14]). Twenty-three patients had repeat samples that were collected 3 to 5 days later. The median for repeat samples was higher at 42.41 µM (IQR [13.08, 62.43]). Patients who were enterally fed had significantly higher levels than those who were not (62.4 ± 7.7 µM vs. 32.4 ± 7.1 µM; p = 0.03). Ascorbic acid levels vary widely among critically ill children with septic shock and/or respiratory failure requiring mechanical ventilation, but one-half of our patients had deficient levels that are typically seen in scurvy. Further studies are warranted to investigate the significance of low levels as well as the impact of normalizing levels through nutritional support.

Mapping genotypes to chromatin accessibility profiles in single cells.

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.

Sports Neuropsychologists' Ratings of Clinical Criteria Used to Help Determine Concussion Recovery: A Brief Survey Report.

OBJECTIVE: To identify criteria used by sports neuropsychologists in determining recovery following sport-related concussion. METHODS: Forty-six sports neuropsychologists completed a custom survey, rating the importance of specific criteria for determining concussion recovery in youth versus adults. Percentages and modal ratings were documented. RESULTS: "Back to work/school without accommodations," "No headache after neurocognitive testing," "Feeling 100% back to normal," and "No symptoms after noncontact exertion" were rated highest for youth and adults. "Physician examination without concerns" and "Balance testing" were the two lowest rated items for both youth and adults. For youth, "sufficient" amount of time symptom-free needed for recovery was seen as longer than for adults. CONCLUSIONS: There was some similarity in how sports neuropsychologists determine concussion recovery for both adults and youth. Future studies should include a larger sample size and concussion experts from other specialties to identify the current multidisciplinary standard of care.

Handheld Lung Ultrasound to Detect COVID-19 Pneumonia in Inpatients: A Prospective Cohort Study.

Background: Chest imaging, including chest X-ray (CXR) and computed tomography (CT), can be a helpful adjunct to nucleic acid test (NAT) in the diagnosis and management of Coronavirus Disease 2019 (COVID-19). Lung point of care ultrasound (POCUS), particularly with handheld devices, is an imaging alternative that is rapid, highly portable, and more accessible in low-resource settings. A standardized POCUS scanning protocol has been proposed to assess the severity of COVID-19 pneumonia, but it has not been sufficiently validated to assess diagnostic accuracy for COVID-19 pneumonia. Purpose: To assess the diagnostic performance of a standardized lung POCUS protocol using a handheld POCUS device to detect patients with either a positive NAT or a COVID-19-typical pattern on CT scan. Methods: Adult inpatients with confirmed or suspected COVID-19 and a recent CT were recruited from April to July 2020. Twelve lung zones were scanned with a handheld POCUS machine. Images were reviewed independently by blinded experts and scored according to the proposed protocol. Patients were divided into low, intermediate, and high suspicion based on their POCUS score. Results: Of 79 subjects, 26.6% had a positive NAT and 31.6% had a typical CT pattern. The receiver operator curve for POCUS had an area under the curve (AUC) of 0.787 for positive NAT and 0.820 for a typical CT. Using a two-point cutoff system, POCUS had a sensitivity of 0.90 and 1.00 compared to NAT and typical CT pattern, respectively, at the lower cutoff; it had a specificity of 0.90 and 0.89 compared to NAT and typical CT pattern at the higher cutoff, respectively. Conclusions: The proposed lung POCUS protocol with a handheld device showed reasonable diagnostic performance to detect inpatients with a positive NAT or typical CT pattern for COVID-19. Particularly in low-resource settings, POCUS with handheld devices may serve as a helpful adjunct for persons under investigation for COVID-19 pneumonia.

Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES).

BACKGROUND: Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery. METHODS: We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major noncardiac surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery. RESULTS: A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to noncardiac surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, P<0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, P=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, P<0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]). CONCLUSIONS: Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before noncardiac surgery.

Synthesis and Characterization of Erbium-Doped Silica Films Obtained by an Acid-Base-Catalyzed Sol-Gel Process.

Erbium-doped silica films were synthesized using a two-step sol-gel methodology that involved acid and base catalysts, with erbium concentration ranging from 0.2% to 6% and annealing temperatures varying from 500 °C to 900 °C. The photoluminescence spectra showed that the samples exhibiting efficient emission were annealed at 800 °C and 900 °C and doped with 3% and 6% erbium. The X-ray diffraction analysis revealed that the internal structure of the films was influenced by the different annealing temperatures and the doping concentrations. Samples with dominant 4f transitions were modelled. The results suggest that the proposed method is a promising approach for the synthesis of erbium-doped silica films with potential applications in optical devices.

Materials Innovations for Quantum Technology Acceleration: A Perspective.

A broad perspective of quantum technology state of the art is provided and critical stumbling blocks for quantum technology development are identified. Innovations in demonstrating and understanding electron entanglement phenomena using bulk and low-dimensional materials and structures are summarized. Correlated photon-pair generation via processes such as nonlinear optics is discussed. Application of qubits to current and future high-impact quantum technology development is presented. Approaches for realizing unique qubit features for large-scale encrypted communication, sensing, computing, and other technologies are still evolving; thus, materials innovation is crucially important. A perspective on materials modeling approaches for quantum technology acceleration that incorporate physics-based AI/ML, integrated with quantum metrology is discussed.

Red Blood Cell Vitamin C Concentration and Its Effect on Deformability in Pediatric Sickle Cell Disease.

Red cell rigidity is common in sickle cell disease (SCD). The contribution of oxidative stress on deformability remains unknown. This study investigated red blood cell (RBC) vitamin C concentrations in pediatric SCD (n=43) compared with healthy controls ( n =23) and developed a protocol to raise RBC vitamin C concentrations to measure the effect on deformability. Sickle cell RBC vitamin C concentrations seem low (20.5 µM, SD: 16.2 vs. 51.7 µM, SD: 15.8; P <0.0001). Vitamin C can be successfully loaded into sickle cell RBCs but seems to have minimal effect on deformability. Future studies are needed to understand the clinical implications of vitamin C deficiency in pediatric SCD.

PARACENTRAL ACUTE MIDDLE MACULOPATHY IN BEHCET DISEASE.

PURPOSE: To report a novel presentation of bilateral paracentral acute middle maculopathy and peripheral vascular occlusions in Behcet disease. METHODS: A retrospective case report with multimodal imaging studies of a patient with Behcet's disease. RESULTS: A 58-year-old Chinese man presented with a paracentral scotoma, fever, arthralgias, and skin rash. Human leukocyte antigen (HLA) typing revealed HLA-B51 positivity. Ophthalmic examination showed peripheral retinal hemorrhages and fluorescein angiography (FA) demonstrated vascular occlusions in the peripheral retina bilaterally. Optical coherence tomography showed classic acute paracentral acute middle maculopathy lesions in both eyes. CONCLUSIONS: Paracentral acute middle maculopathy and peripheral vascular occlusion are infrequent and unconventional presentations of Behcet disease. To the best of our knowledge, this is the first report in the ophthalmic literature of paracentral acute middle maculopathy and peripheral vascular occlusion in Behcet disease.

Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms.

PURPOSE: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation. EXPERIMENTAL DESIGN: Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non-small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation. RESULTS: We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN. CONCLUSIONS: In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

A Tale of Progressive Painless Vision Loss in a 64-Year-Old Man Due to Leber Hereditary Optic Neuropathy.

ABSTRACT: A 64-year-old man presented with painless sequential bilateral vision loss, consistent with optic neuropathy, over the span of months. The significant decline in his visual function was out of proportion to the appearance of the optic nerves (which were not pale) or changes in his retinal nerve fiber layer thickness on optical coherence tomography. Neuroimaging revealed only mild T2 signal abnormality and faint enhancement in the left optic nerve. Extensive workup for potential infectious, metabolic, inflammatory, and ischemic etiologies was unremarkable. Empiric treatment with intravenous steroids did not slow or ameliorate the vision loss. Ultimately, genetic analysis revealed a missense m.11778G>A mutation in mitochondrial MT-ND4 gene, consistent with Leber hereditary optic neuropathy. Initiation of multivitamin supplements and idebenone unfortunately did not result in recovery of vision.

Transboundary aerosol transport process and its impact on aerosol-radiation-cloud feedbacks in springtime over Northeast Asia.

Northeast Asia has been suffering from dramatic increases of particulate matter (PM) since the late 1990s, and it still continues to undergo haze despite various abating regulations. In this study, we investigated aerosol-cloud-precipitation (ACP) interactions with the varied PM, and the impact of long-range transport (LRT) process on ACP in springtime was assessed in Northeast Asia. Our long-term (1995-2019) analysis of PM10 exhibited the correlation with decreases of both sunshine duration and drizzle occurrences that can be interpreted as direct and indirect aerosol effects, while cloud cover induced by the varied PM10 was found only in more than 90% cloud cover (9/10-10/10 category). The online WRF-Chem with wind-blown dust simulation indicated that cloud water was affected by secondary inorganic aerosol (SIA) formation near the surface in upwind areas dominantly, whereas, along the LRT pathway, cloud water perturbation altitudes were increased quasi-linearly toward downward between 1 and 3 km. The gas-to-particle conversion ratios of sulfur ([SO42-]/[SO2 + SO42-]) and nitrogen ([NO3-]/[NO2 + NO3-]) both remain aloft long at the same vertical levels of most perturbed cloud altitude enough to be transported over long distance in springtime. Formations of sulfate and nitrate showed different ACP interaction timing; distinctive shifts in the ratios observed at the exit (Shanghai-Yellow Sea) by nitrate, and entrance areas (Seoul-Tokyo) by sulfate along the LRT pathway, respectively, with higher ratios of 0.8 or more in springtime. Our results indicate that ACP processes have been enhanced at a LRT-related altitude with different SIA production timings that can be considered in species-specific springtime PM abatements over Northeast Asia.