Long non-coding RNA lung cancer-associated transcript-1 promotes glioblastoma progression by enhancing Hypoxia-inducible factor 1 alpha activity.

BACKGROUND: Hypoxia is associated with poor prognosis in many cancers including glioblastoma (GBM). Glioma stem-like cells (GSCs) often reside in hypoxic regions and serve as reservoirs for disease progression. Long non-coding RNAs (lncRNAs) have been implicated in GBM. However, the lncRNAs that modulate GSC adaptations to hypoxia are poorly understood. Identification of these lncRNAs may provide new therapeutic strategies to target GSCs under hypoxia. METHODS: lncRNAs induced by hypoxia in GSCs were identified by RNA-seq. Lung cancer-associated transcript-1 (LUCAT1) expression was assessed by qPCR, RNA-seq, Northern blot, single molecule FISH in GSCs, and interrogated in IvyGAP, The Cancer Genome Atlas, and CGGA databases. LUCAT1 was depleted by shRNA, CRISPR/Cas9, and CRISPR/Cas13d. RNA-seq, Western blot, immunohistochemistry, co-IP, ChIP, ChIP-seq, RNA immunoprecipitation, and proximity ligation assay were performed to investigate mechanisms of action of LUCAT1. GSC viability, limiting dilution assay, and tumorigenic potential in orthotopic GBM xenograft models were performed to assess the functional consequences of depleting LUCAT1. RESULTS: A new isoform of Lucat1 is induced by Hypoxia inducible factor 1 alpha (HIF1α) and Nuclear factor erythroid 2-related factor 2 (NRF2) in GSCs under hypoxia. LUCAT1 is highly expressed in hypoxic regions in GBM. Mechanistically, LUCAT1 formed a complex with HIF1α and its co-activator CBP to regulate HIF1α target gene expression and GSC adaptation to hypoxia. Depletion of LUCAT1 impaired GSC self-renewal. Silencing LUCAT1 decreased tumor growth and prolonged mouse survival in GBM xenograft models. CONCLUSIONS: A HIF1α-LUCAT1 axis forms a positive feedback loop to amplify HIF1α signaling in GSCs under hypoxia. LUCAT1 promotes GSC self-renewal and GBM tumor growth. LUCAT1 is a potential therapeutic target in GBM.

VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.

Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

Chronic hypoxia stabilizes 3ßHSD1 via autophagy suppression.

Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration-resistant prostate cancer (CRPC), which remains driven by non-gonadal androgens synthesized in prostate cancer tissues. 3ß-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3ßHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3ßHSD1, especially the "adrenal-permissive" 3ßHSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3ßHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3ßHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3ßHSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells.

Tranexamic acid for angiotensin-converting enzyme inhibitor-induced angioedema.

Approximately 0.7% of patients taking angiotensin-converting enzyme inhibitors (ACEIs) develop ACEI-induced angioedema (ACEI-IA). With no approved treatments for ACEI-IA, the risk of complications is concerning. Tranexamic acid (TXA) has the potential to prevent intubations and resolve ACEI-IA by inhibiting the downstream production of bradykinin. In this review, we aim to evaluate the safety and efficacy of TXA use in ACEI-IA. We queried the PubMed database for studies involving TXA for ACEI-IA from January 2003 to January 2023. Seven studies met the study inclusion criteria. Our results demonstrate that TXA may improve angioedema symptoms and prevent intubation. In addition, its availability, low cost, and safety profile support its use for improving the symptoms and complications of ACEI-IA in an emergency setting.

Intratumoral androgen biosynthesis associated with 3ß-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer.

Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3ßHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3ßHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3ßHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.

Supergrowth and sub-wavelength object imaging.

We further develop the concept of supergrowth [Quantum Stud.: Math. Found.7, 285 (2020)10.1007/s40509-019-00214-5], a phenomenon complementary to superoscillation, defined as the local amplitude growth rate of a function higher than its largest wavenumber. We identify a canonical oscillatory function's superoscillating and supergrowing regions and find the maximum values of local growth rate and wavenumber. Next, we provide a quantitative comparison of lengths and relevant intensities between the superoscillating and the supergrowing regions of a canonical oscillatory function. Our analysis shows that the supergrowing regions contain intensities that are exponentially larger in terms of the highest local wavenumber compared to the superoscillating regions. Finally, we prescribe methods to reconstruct a sub-wavelength object from the imaging data using both superoscillatory and supergrowing point spread functions. Our investigation provides an experimentally preferable alternative to the superoscillation-based superresolution schemes and is relevant to cutting-edge research in far-field sub-wavelength imaging.

Minimally invasive approach associated with lower resource utilization after aortic and mitral valve surgery.

Objective: To investigate the effect of minimally invasive cardiac surgery (MICS) on resource utilization, cost, and postoperative outcomes in patients undergoing left-heart valve operations. Methods: Data were retrospectively reviewed for patients undergoing single-valve surgery (eg, aortic valve replacement, mitral valve replacement, or mitral valve repair) at a single center from 2018 to 2021, stratified by surgical approach: MICS vs full sternotomy (FS). Baseline characteristics and postoperative outcomes were compared. Primary outcome was high resource utilization, defined as direct procedure cost higher than the third quartile or either postoperative LOS ≥7 days or 30-day readmission. Secondary outcomes were direct cost, length of stay, 30-day readmission, in-hospital and 30-day mortality, and major morbidity. Multiple regression analysis was conducted, controlling for baseline characteristics, operative approach, valve operation, and lead surgeon to assess high resource utilization. Results: MICS was correlated with a significantly lower rate of high resource utilization (MICS, 31.25% [n = 115] vs FS 61.29% [n = 76]; P < .001). Median postoperative length of stay (MICS, 4 days [range, 3-6 days] vs FS, 6 days [range, 4 to 9 days]; P < .001) and direct cost (MICS, $22,900 [$19,500-$28,600] vs FS, $31,900 [$25,900-$50,000]; P < .001) were lower in the MICS group. FS patients were more likely to experience postoperative atrial fibrillation (P = .040) and renal failure (P = .027). Other outcomes did not differ between groups. Controlling for stratified Society of Thoracic Surgeons predicted risk of mortality, cardiac valve operation, and lead surgeon, FS demonstrated increased likelihood of high resource utilization (P < .001). Conclusions: MICS for left-heart valve pathology demonstrated improved postoperative outcomes and resource utilization.

Marine estuaries act as better sink for greenhouse gases during winter in undisturbed mangrove than degraded ones in Sundarban, India.

The estuaries provide the key pathway for travelling carbon across the land-ocean interfaces and behave as both source and sink of greenhouse gases (GHGs) in water-atmosphere systems. The sink-source characteristics of estuaries for GHGs vary spatially. The primary driving factors are adjacent ecologies (agriculture, aquaculture, etc.) and proximities to the sea. To study the sink-source characteristics of estuaries for GHGs (methane (CH4), nitrous oxide (N2O) and carbon dioxide (CO2)), the water samples were collected from 53 different locations in the estuaries for estimation of dissolved GHGs concentration and air-water GHGs exchanges. The locations represent five zones (Zone I, II, III, IV and V) based on the type and degradation status of mangroves (degraded and undisturbed), anthropogenic activities, and distance from the sea. Zone I, III, V represents to the degraded mangroves far from sea, whereas, Zone II, IV surrounded by undisturbed mangroves and nearer to sea. The average dissolved CH4 concentrations were higher in the estuaries which were adjacent to degraded mangroves (154.4 nmol L-1) than undisturbed mangroves (81.7 nmol L-1). Further, the average dissolved N2O concentrations were 48% higher in the estuaries nearer to degraded mangroves than that of undisturbed ones. Among the degraded mangrove sites, the dissolved CO2 concentrations were higher at Zone I (30.1 µmol L-1) followed by Zone III and IV, whereas in undisturbed sites, it was higher in Zone IV (22.3 µmol L-1) than Zone II (17.6 µmol L-1). Among the 53 locations, 36, 51 and 33 locations acted as a sink (negative value of exchanges) for CH4, N2O and CO2, respectively. The higher sink potential for CH4 was recorded to those estuaries adjacent to undisturbed mangroves (-791.69 µmol m-2 d-1) than the degraded ones (-23.18 µmol m-2 d-1). Similarly, the average air-water N2O and CO2 exchanges were more negative in the estuaries which were nearer to undisturbed mangroves indicating higher sink potential. The pH, and salinity of the estuary water were negatively correlated with air-water CH4 and N2O exchanges, whereas those were positively correlated with CO2 exchanges. Significantly lower dissolved GHGs and air-water GHGs exchange was observed in the estuaries adjacent to the undisturbed mangrove as compared to the degraded mangrove. The reason behind higher sink behaviours of estuaries nearer to undisturbed mangroves are higher intrusion of seawater, less nutrient availability, higher salinity, low carbon contents and alkaline pH compared to estuaries adjacent to degraded mangroves and far from sea.

Monitoring early-season agricultural drought using temporal Sentinel-1 SAR-based combined drought index.

Early-season agricultural drought is frequent over South Asian region due to delayed or deficient monsoon rainfall. These drought events often cause delay in sowing and can even result in crop failure. The present study focuses on monitoring early-season agricultural drought in a semi-arid region of India over 5-year period (2016-2020). It utilizes hydro-climatic and biophysical variables to develop a combined drought index (CDI), which integrates anomalies in soil moisture conditions, rainfall, and crop-sown area progression. Synthetic aperture radar (SAR)-based soil moisture index (SMI) represents in situ measured soil moisture with reasonable accuracy (r=0.68). Based on the highest F1-score, SAR backscatter in VH (vertical transmit-horizontal receive) polarization with specific values for parameter threshold (-18.63 dB) and slope threshold (-0.072) is selected to determine the start of season (SoS) with a validation accuracy of 73.53%. The CDI approach is used to monitor early-season agricultural drought and identified drought conditions during June-July in 2019 and during July in 2018. Conversely, 2020 experienced consistently wet conditions, while 2016 and 2017 had near-normal conditions. Overall, the study highlights the use of SAR data for early-season agricultural drought monitoring, which is mainly governed by soil moisture-driven crop-sowing progression. The proposed methodology holds potential for effective monitoring, management, and decision-making in early-season agricultural drought scenarios.

Trace elements in ambient aerosols and size-resolved fog droplets: Trends, enrichment, and risk assessment.

Ambient particulate matter (PM) is composed of inorganic and organic components. The contribution of each component is impacted by various factors such as emission sources, atmospheric aging process, and size of the PM or droplets. This study mainly focuses on the effect of the PM and droplet size on trace elemental concentrations, for which various size fractions of ambient PM (PM1, PM2.5) were collected on quartz filters along with fog water (FW) samples during winter. Simultaneous, online measurements of the mass concentrations of PM1 and PM2.5 were also carried out. At the time of the collection, the mass concentration of PM2.5 ranged from 19 to 890 µg/m3, and its mean value was 227 µg/m3. During the sampling period, 17 fog events occurred and caused a 27% reduction in the mean pre-fog PM2.5 concentration. All the PM and FW samples were analyzed for 12 trace elements: Ca, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Zn, V. The concentrations of the various trace elements in the PM1, PM2.5, and FW samples encompassed a wide range: 10 (V)-2432 (Na) ng/m3, 34 (Mn)-13810 (Na) ng/m3, and 8 (Cr)-19870 (Ca) µg/l, respectively. The concentrations of the trace elements in the FW samples indicated a droplet-size-dependent trend: the small droplets (diameter <16 µm) had several times (3-10 times) higher concentrations than the coarser droplets (diameter >22 µm). The enrichment factor (EF) analysis revealed that the EF values for almost all the trace elements were an order of magnitude higher in the FW samples than in PM1 and PM2.5. Risk assessment based on toxic elements suggested a very high inhalation carcinogenic risk (231 per million) for the exposed population during foggy periods. This study will facilitate decision-making by policymakers regarding air quality and health concerns.

Immunobiology and Metabolic Pathways of Renal Cell Carcinoma.

The treatment of advanced renal cell carcinoma (RCC) has changed dramatically with immune checkpoint inhibitors, yet most patients do not have durable responses. There is consequently a tremendous need for novel therapeutic development. RCC, and particularly the most common histology clear cell RCC, is an immunobiologically and metabolically distinct tumor. An improved understanding of RCC-specific biology will be necessary for the successful identification of new treatment targets for this disease. In this review, we discuss the current understanding of RCC immune pathways and metabolic dysregulation, with a focus on topics important for future clinical development.

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.

Non-invasive ventilation usage and adherence in children and adults with Duchenne muscular dystrophy: A multicenter analysis.

INTRODUCTION/AIMS: Non-invasive ventilation (NIV) is routinely prescribed to support the respiratory system in Duchenne muscular dystrophy (DMD) patients; however, factors improving NIV usage are unclear. We aimed to identify predictors of NIV adherence in DMD patients. METHODS: This was a multicenter retrospective analysis of DMD patients prescribed NIV and followed at (1) The Hospital for Sick Children, Canada; (2) Rady Children's Hospital San Diego, USA; and (3) University of California San Diego Health, USA, between February 2016 and October 2020. The primary and secondary outcomes were 90-day period NIV adherence and clinical and socioeconomic predictors of NIV adherence. RESULTS: We identified 59 DMD patients prescribed NIV (mean ± SD age = 20.1 ± 6.7 y). Overall, percentage of nights used, and average nightly usage, were 79.9 ± 31.1% and 7.23 ± 4.12 h, respectively. Compared with children, adults had higher percentage of nights used (92.9 ± 16.9% vs. 70.4 ± 36.9%; P < .05), and average nightly usage (9.5 ± 4.7 h vs. 5.3 ± 3.7 h; P < .05). Non-English language (P = .01), and absence of deflazacort prescription (P = .02) were significantly associated with higher percentage of nights used while Hispanic ethnicity (P = .01), low household income (P = .02), and absence of deflazacort prescription (P = .02) were significantly associated with higher nightly usage. Based on univariable analysis, older age and declining forced vital capacity were associated with increased percentage of nights used and increased average nightly usage. DISCUSSION: Certain clinical and socioeconomic determinants had a significant impact on NIV adherence in DMD patients, providing insight into those at risk for high versus low compliance with respiratory therapy.

Vitmain B12 as Severity and Prognostic Marker in Chronic Liver Disease.

INTRODUCTION: Chronic liver disease is an immuno-compromised state is well known established fact but there are falsely elevated vitamin B12 levels in patients with chronic liver disease, which can be used as severity and prognostic marker. This study was designed to investigate the association between vitamin B12 levels and liver disease severity and long term prognosis in patients with chronic liver disease. MATERIALS: An observational longitudinal study was carried over a period of 6 months among indoor patients admitted in department of medicine of a tertiary care hospital in North-Eastern India. A total of 50 patients diagnosed with chronic liver disease were enrolled. Serum vitamin B12 concentration and other blood parameters were determined. The data were analyzed accordingly by descriptive statistics using Spss for the result. RESULT: The study population were predominantly male with mean age 50.80 ± 10.35. Mean total serum vitamin B12 concentration was significantly higher in patients with chronic liver disease (1639 ± 504 pg/ml) when compared to normal people (650 ± 300pg/ml). Also among patients with chronic liver disease Child-Pugh C (1858 ± 359pg/mL) had higher B12 levels when compared to those with Child-Pugh B (1076 ± 370 pg/mL). Out of 50 people, 4 were died and their mean B12 was (2113 ± 112 pg/ml). CONCLUSION: Falsely increased B12 levels are due to increased excretion of vitamin B12 in to serum from the liver and these serum B12 levels correlates with the severity and prognosis of the patient. References Sugihara T, Koda M, Okamoto T, et al. Falsely elevated serum vitamin B12 levels were associated with the severity and prognosis of chronic viral liver disease. Yonago Acta Med 2017;60(1):31-39. Dou J, Xu W, Ye B, et al. Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acute-on-chronic liver failure. Clin Chim Acta 2012;413(23-24):1809-1812.

Incidence of Acute Neurological Events in Neonates and Infants Undergoing Cardiac Surgery Using a High-Hematocrit/ High-Flow Bypass Strategy.

Background: The incidence of new acute neurological injury occurring in neonates and infants during cardiac surgery utilizing cardiopulmonary bypass is reportedly 3% to 5%. In 2013, we adopted a high flow rate, and high hematocrit bypass strategy, and sought to assess the incidence of early neurological injuries associated with this strategy. Methods: Neonates and infants undergoing cardiopulmonary bypass between January 2013 and December 2019 (n = 714) comprise the study. Adverse neurological events (ANEs) were defined as any abnormality of pupils, delayed awakening, seizures, focal neurological deficits, concerns prompting neurological consultation, or any abnormality on neurological imaging in the postoperative period. Our bypass strategy included a high flow rate (150-200 mL/kg/min), without reduction of flow rates during cooling and maintaining a target hematocrit on bypass > 32% with a terminal hematocrit of > 42%. Results: Median weight at the time of the procedure was 4.6 kg (IQR 3.6-6.1 kg) with the smallest patient weighing 1.36 kg. There were 46 premature patients (6.4%). There were 149 patients (20.9%) patients who underwent deep hypothermic circulatory arrest with a median time of 26 min (IQR 21-41 min). Hospital mortality was 3.5% (24/714, 95% CI: 2.28-5.13). The incidence of neurological events as defined above was 0.84% (6/714, 95% CI: 0.31-1.82). Neurological imaging identified ischemic injury in 4 patients and intraventricular hemorrhage in 2. Conclusions: High flow/high hematocrit bypass strategy was associated with a low incidence of ANE in this vulnerable population.

Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis.

Nocturnal hypoxaemia, which is common in chronic obstructive pulmonary disease (COPD) patients, is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day, in contrast to recurrent brief hypoxic episodes during obstructive sleep apnoea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by three cycles of 8 h hypoxia followed by 16 h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72 h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, and of GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggest an adaptive exhaustion with failure to restore homeostasis during normoxia. KEY POINTS: Sarcopenia or skeletal muscle loss is one of the most frequent complications that contributes to mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). Unlike chronic hypoxia, prolonged intermittent hypoxia is a frequent, underappreciated and clinically relevant model of hypoxia in patients with COPD. We developed a novel, in vitro myotube model of prolonged intermittent hypoxia with molecular and metabolic perturbations, mitochondrial oxidative dysfunction, and consequent sarcopenic phenotype. In vivo studies in skeletal muscle from a mouse model of COPD shared responses with our myotube model, establishing the pathophysiological relevance of our studies. These data lay the foundation for translational studies in human COPD to target prolonged, nocturnal hypoxaemia to prevent sarcopenia in these patients.

Long-Term Cardiovascular Outcomes of Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Using an Institution Based Algorithm.

Cardiovascular involvement is a major cause of inpatient and intensive care unit morbidity related to Multisystem inflammatory syndrome in children (MIS-C). The objective of this study was to identify long-term cardiovascular manifestations of MIS-C. We included 80 consecutive patients admitted to the intensive care unit with MIS-C who were evaluated for a year in our follow-up clinic using an institution protocol. The outcome measures were cardiac biomarkers (troponin and BNP), electrocardiogram changes, echocardiographic findings cardiovascular magnetic resonance (CMR) and graded-exercise stress test (GXT) findings. The cohort included patients aged between 6 months and 17 years (median 9 years; 48.8% females). At the peak of the disease 81.3% had abnormal BNP and 58.8% had troponin leak which reduced to 33.8% and 18.8% respectively at discharge with complete normalization by 6 weeks post-discharge. At admission 33.8% had systolic dysfunction, which improved to 11.3% at discharge with complete resolution by 2 weeks. Coronary artery abnormalities were seen in 17.5% during the illness with complete resolution by 2 weeks post discharge except one (1.9%) with persistent giant aneurysm at 1 year-follow up. CMR was performed at 6 months in 23 patient and demonstrated 4 patients with persistent late gadolinium enhancement (17.4%). Normal exercise capacity with no ectopy was seen in the 31 qualifying patients that underwent a GXT. There is significant heterogeneity in the cardiovascular manifestations of MIS-C. Although majority of the cardiovascular manifestations resolve within 6 weeks, diastolic dysfunction, CAA and myocardial scar may persist in a small subset of patients warranting a structured long-term follow-up strategy.

Selumetinib for Refractory Pulmonary and Gastrointestinal Bleeding in Noonan Syndrome.

A 15-year-old-boy with Noonan syndrome and status post orthoptic heart transplant developed mixed mitral valve disease and underwent mechanical mitral valve replacement 6 months before presentation with acute respiratory distress. He developed massive pulmonary hemorrhage that required veno-venous extracorporeal membrane oxygenation (ECMO) support. He had a prolonged anticoagulation free ECMO course of 4 weeks, with ongoing recurrent pulmonary hemorrhage and underwent several rounds of coil embolization of aortopulmonary collaterals. ECMO course was complicated by significant nasopharyngeal bleeding that required embolization of the sphenopalatine artery. Shortly after decannulation, he developed massive gastrointestinal and peritoneal hemorrhage that was treated by embolization of the left gastric artery and a branch of the internal iliac artery. His bleeding was attributed to neo-angiogenesis. Initial treatment with propranolol was unsuccessful. Subsequent treatment with interferon α 2b demonstrated efficacy, but severe neutropenia required cessation of therapy. Because functional alterations of the rat sarcoma virus-mitogen activated protein kinase signaling pathway and protein tyrosine phosphatase nonreceptor type (PTPN11) mutations in Noonan syndrome are known to be associated with neo-angiogenesis, we used the mitogen-activated protein kinase inhibitor selumetinib as a gene-targeted therapy with the hope of controlling bleeding and inhibiting neo-angiogenesis. After initiation of selumetinib, bleeding stopped and allowed the patient to be discharged from the hospital on dipyridamole as antiplatelet prophylaxis for his mechanical mitral valve. He had no further bleeding episodes through 1 year after hospital discharge.

Light absorption potential of water-soluble organic aerosols in the two polluted urban locations in the central Indo-Gangetic Plain.

PM2.5 (particulate matter having aerodynamic diameter ≤2.5 µm) samples were collected during wintertime from two polluted urban sites (Allahabad and Kanpur) in the central Indo-Gangetic Plain (IGP) to comprehend the sources and atmospheric transformations of light-absorbing water-soluble organic aerosol (WSOA). The aqueous extract of each filter was atomized and analyzed in a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). Water-soluble organic carbon (WSOC) and WSOA concentrations at Kanpur were ∼1.2 and ∼1.5 times higher than that at Allahabad. The fractions of WSOC and secondary organic carbon (SOC) to total organic carbon (OC) were also significantly higher ∼53% and 38%, respectively at Kanpur compared to Allahabad. This indicates a higher abundance of oxidized WSOA at Kanpur. The absorption coefficient (babs-365) of light-absorbing WSOA measured at 365 nm was 46.5 ± 15.5 Mm-1 and 73.2 ± 21.6 Mm-1 in Allahabad and Kanpur, respectively, indicating the dominance of more light-absorbing fractions in WSOC at Kanpur. The absorption properties such as mass absorption efficiency (MAE365) and imaginary component of refractive index (kabs-365) at 365 nm at Kanpur were also comparatively higher than Allahabad. The absorption forcing efficiency (Abs SFE; indicates warming effect) of WSOA at Kanpur was ∼1.4 times higher than Allahabad. Enhancement in light absorption capacity was observed with the increase in f44/f43 (fraction of m/z 44 (f44) to 43 (f43) in organic mass spectra) and O/C (oxygen to carbon) ratio of WSOA at Kanpur while no such trend was observed for the Allahabad site. Moreover, the correlation between carbon fractions and light absorption properties suggested the influence of low-volatile organic compounds (OC3 + OC4 fraction obtained from thermal/optical carbon analyzer) in increasing the light absorption capacity of WSOA in Kanpur.