Citations

Introduction High-dose catecholamines can impair hypoxic pulmonary vasoconstriction and increase shunt fraction. We aimed to determine if Angiotensin II (Ang-2) is associated with improved PaO 2 /FiO 2 and SpO 2 /FiO 2 in patients in shock. Methods Adult patients at four tertiary care centers and one community hospital in the United States who received Ang-2 from July 2018-September 2020 were included in this retrospective, observational cohort study. PaO 2 , SpO 2 , and FiO 2 were measured at 13 timepoints during the 48-h before and after Ang-2 initiation. Piecewise linear mixed models of PaO 2 /FiO 2 and SpO 2 /FiO 2 were created to evaluate hourly changes in oxygenation after Ang-2 initiation. The difference in the proportion of patients with PaO 2 /FiO 2 ≤ 300 mm Hg at the time of Ang-2 initiation and 48 h after was also examined. Results The study included 254 patients. In the 48 h prior to Ang-2 initiation, oxygenation was significantly declining (hourly PaO 2 /FiO 2 change −4.7 mm Hg/hr, 95% CI − 6.0 to −3.5, p < .001; hourly SpO 2 /FiO 2 change −3.1/hr, 95% CI−3.7 to −2.4, p < .001). Ang-2 treatment was associated with significant improvements in PaO 2 /FiO 2 and SpO 2 /FiO 2 in the 48-h after initiation (hourly PaO 2 /FiO 2 change +1.5 mm Hg/hr, 95% CI 0.5-2.5, p = .003; hourly SpO 2 /FiO 2 change +0.9/hr, 95% CI 0.5-1.2, p < .001). The difference in the hourly change in oxygenation before and after Ang-2 initiation was also significant ( p interaction < 0.001 for both PaO 2 /FiO 2 and SpO 2 /FiO 2 ). This improvement was associated with significantly fewer patients having a PaO 2 /FiO 2 ≤ 300 mm Hg at 48 h compared to baseline (mean difference −14.9%, 95% CI −25.3% to −4.6%, p = .011). Subgroup analysis found that patients with either a baseline PaO 2 /FiO 2 ≤ 300 mm Hg or a norepinephrine-equivalent dose requirement >0.2 µg/kg/min had the greatest associations with oxygenation improvement. Conclusions Ang-2 is associated with improved PaO 2 /FiO 2 and SpO 2 /FiO 2 . The mechanisms for this improvement are not entirely clear but may be due to catecholamine-sparing effect or may also be related to improved ventilation-perfusion matching, intrapulmonary shunt, or oxygen delivery.

The radiotracer 1‐(2‐[18F]fluoroethyl)‐L‐tryptophan (L‐[18F]FETrp or [18F]FETrp) is a substrate of indoleamine 2,3‐dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [18F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first‐in‐human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18F]FETrp on a Synthra RNPlus research module, including a one‐pot two steps radiosynthesis, dual independent chiral and reverse‐phase semipreparative high‐performance liquid chromatography purifications, and solid‐phase extraction‐assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans.

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.

Abstract Introduction: Immune checkpoint blockade (ICB) has clinical activity in triple negative breast cancer (TNBC) but is less effective in the ER+HER2- signature, where there is a cold immune microenvironment (IM) and regulatory T cells (Tregs) may suppress effector T cells. Agents that activate the IM by turning cold tumors hot may support ICB. The biguanides hexyl-benzyl-biguanide (HBB) and its bioisostere hexyl-(cuban-1-yl-methyl)-biguanide (HCB) are candidate agents to activate the IM because they potently inhibit biosynthesis of immunosuppressive epoxyeicosatrienoic acids (EETs) and EET-driven oxidative phosphorylation (OXPHOS), while blocking N-glycosylation of immune checkpoint (IC) proteins. We hypothesized that reversal of hypoxia by biguanides in the ovarian dependent ER+HER2- STAT1 KO SSM2ucd mouse mammary carcinoma (MC) model would suppress Tregs and promote effector T cells in the tumor IM. While the SSM2ucd model did not express immune checkpoint protein PD-L1 (B7-H1), it did express related IC proteins B7-H3 and B7-H4. We hypothesized that by inhibiting OXPHOS and reducing N-glycosylation of immune checkpoint proteins, HBB and HCB may promote efficacy of ICB. We chose the SSM2ucd model to test impact of HCB on the ER+ MC IM. Results: SSM2ucd cells exhibited longer tumor latency (60 days) than the basal 4T1 (10 days) and 67NR (20 days) mouse MC models. SSM2ucd tumor reimplantation shortened latency by more than half, to 20 days. Immunohistochemistry showed that B7-H3 and B7-H4 protein levels were 1.2 (P=0.001) and 1.3-fold (P=0.04) higher in reimplanted tumors vs. control. In SSM2ucd cells, HCB inhibited N-glycosylation of B7-H3 (P=0.01) by 35% and B7-H4 (P=0.02) by 45% and suppressed TGFβ induction of B7-H3 by 21% (P=0.02) and B7-H4 by 79% (P=0.001) at 24 hours, while 14,15-EET promoted N-glycosylation of B7-H3 (1.2-fold; P=0.03) and B7-H4 (1.3-fold; P=0.04) at 4 hours. Effects of HBB and HCB on anti-CD3 and anti-CD28 stimulated mouse splenocytes were assayed. The proliferative effects of HBB on CD4+ and CD8+ cells peaked at 12 uM (p&lt;0.001) and for HCB at 6.25 uM (p&lt;0.001). Tregs decreased with HCB at a threshold of 12 uM (p &lt;0.001) and with HBB at 25 uM (P &lt; 0.001) while 14,15-EET increased Tregs (1.2 fold; P=0.02) and suppressed the CD8+:Treg ratio (0.79; P=0.02). In the SSM2ucd mammary allograft model, although HCB 12mg/kg daily did not inhibit tumor growth, it reduced intratumoral hypoxia by 20% (P=0.01), increased CD8+ TIL by 4.4-fold (P=0.04), decreased Treg:CD4+ TIL ratio by 76% (P=0.02), and decreased Treg:CD8+ TIL ratio by 88% (P=0.01) relative to control. Conclusion: B7-H3 and B7-H4 expression inversely correlated with latency of ER+ MC and may represent targets for immune checkpoint antibodies and their drug conjugates. HCB, an inhibitor of OXPHOS and EET biosynthesis, reduced intratumoral hypoxia, increased CD8+ TIL and reduced the Treg:CD8+ ratio, potentially supporting ICB therapy of ER+ MC by turning cold tumors hot. Supported by CDMRP BCRP Grant BC180596, Award Number W81XWH-19-1-0099 Citation Format: Zhijun Guo, Jianxun Lei, Hrishi Venkatesh, David Owen, Adam Bass, Christine Cannon, Joshua McCarra, Brenda Koniar, Craig Flory, Beverly Norris, Robert J. Schumacher, Swaathi Jayaraman, John Hawse, Emmanuel S. Antonarakis, Emanuel F. Petricoin, Julia Wulfkuhle, Robert D. Cardiff, Elizabeth A. Ambrose, Gunda I. Georg, Kaylee L. Schwertfeger, Michael A. Farrar, Brad St. Croix, Matthew P. Goetz, David A. Potter. Hexyl-(cuban-1-yl-methyl)-biguanide (HCB) suppresses N-glycosylation of immune checkpoint proteins B7-H3 and B7-H4, reverses tumor hypoxia, decreases intratumoral regulatory T cells, and increases intratumoral CD8+ T cells in the ovarian dependent ER+HER2- SSM2ucd mammary cancer allograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB102.

This scientific commentary refers to ‘Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic’ by Wong et al. (https://doi.org/10.1093/brain/awad031).

Multiplex immunofluorescence (MxIF) images provide detailed information of cell composition and spatial context for biomedical research. However, compromised data quality could lead to research biases. Comprehensive image quality checking (QC) is essential for reliable downstream analysis. As a reliable and specific staining of cell nuclei, 4′,6-diamidino-2-phenylindole (DAPI) signals were used as references for tissue localization and auto-focusing across MxIF staining–scanning–bleaching iterations and could potentially be reused for QC. To confirm the feasibility of using DAPI as QC reference, pixel-level DAPI values were extracted to calculate signal fluctuations and tissue content similarities in staining–scanning–bleaching iterations for identifying quality issues. Concordance between automatic quantification and human experts’ annotations were evaluated on a data set consisting of 348 fields of view (FOVs) with 45 immune and tumor cell markers. Cell distribution differences between subsets of QC-pass vs QC-failed FOVs were compared to investigate the downstream effects. Results showed that 87.3% FOVs with tissue damage and 73.4% of artifacts were identified. QC-failed FOVs showed elevated regional gathering in cellular feature space compared with the QC-pass FOVs. Our results supported that DAPI signals could be used as references for MxIF image QC, and low-quality FOVs identified by our method must be cautiously considered for downstream analyses.

Abstract OBJECTIVES The prevalence and aetiology of acute aortic dissection type A (AADA) in patients ≤30 years is unknown. The aims of this clinical study were to determine the prevalence and potential aetiology of AADA in surgically treated patients ≤30 years and to evaluate the respective postoperative outcomes in this selective group of patients in a large multicentre study. METHODS Retrospective data collection was performed at 16 participating international aortic institutions. All patients ≤30 years at the time of dissection onset were included. The postoperative results were analysed with regard to connective tissue disease (CTD). RESULTS The overall prevalence of AADA ≤30 years was 1.8% (139 out of 7914 patients), including 51 (36.7%) patients who were retrospectively diagnosed with CTD. Cumulative postoperative mortality was 8.6%, 2.2% and 1.4%. Actuarial survival was 80% at 10 years postoperatively. Non-CTD patients (n = 88) had a significantly higher incidence of arterial hypertension (46.6% vs 9.8%; P &lt; 0.001) while AADA affected the aortic root (P &lt; 0.001) and arch (P = 0.029) significantly more often in the CTD group. A positive family history of aortic disease was present in 9.4% of the study cohort (n = 13). CONCLUSIONS The prevalence of AADA in surgically treated patients ≤30 years is &lt;2% with CTD and arterial hypertension as the 2 most prevalent triggers of AADA. Open surgery may be performed with good early results and excellent mid- to long-term outcomes.

Infectious diseases contribute significantly to the global disease burden. Sensitive and accurate screening methods are some of the most effective means of identifying sources of infection and controlling infectivity. Conventional detecting strategies such as quantitative polymerase chain reaction (qPCR), DNA sequencing, and mass spectrometry typically require bulky equipment and well-trained personnel. Therefore, mass screening of a large population using conventional strategies during pandemic periods often requires additional manpower, resources, and time, which cannot be guaranteed in resource-limited settings. Recently, emerging microfluidic technologies have shown the potential to replace conventional methods in performing point-of-care detection because they are automated, miniaturized, and integrated. By exploiting the spatial separation of detection sites, microfluidic platforms can enable the multiplex detection of infectious diseases to reduce the possibility of misdiagnosis and incomplete diagnosis of infectious diseases with similar symptoms. This review presents the recent advances in microfluidic platforms used for multiplex detection of infectious diseases, including microfluidic immunosensors and microfluidic nucleic acid sensors. As representative microfluidic platforms, lateral flow immunoassay (LFIA) platforms, polymer-based chips, paper-based devices, and droplet-based devices will be discussed in detail. In addition, the current challenges, commercialization, and prospects are proposed to promote the application of microfluidic platforms in infectious disease detection.

Purpose: Quantitative biomarkers from chest computed tomography (CT) can facilitate the incidental detection of important diseases. Atrial fibrillation (AFib) substantially increases the risk for comorbid conditions including stroke. This study investigated the relationship between AFib status and left atrial enlargement (LAE) on CT. Materials and Methods: A total of 500 consecutive patients who had undergone nongated chest CTs were included, and left atrium maximal axial cross-sectional area (LA-MACSA), left atrium anterior-posterior dimension (LA-AP), and vertebral body cross-sectional area (VB-Area) were measured. Height, weight, age, sex, and diagnosis of AFib were obtained from the medical record. Parametric statistical analyses and receiver operating characteristic curves were performed. Machine learning classifiers were run with clinical risk factors and LA measurements to predict patients with AFib. Results: Eighty-five patients with a diagnosis of AFib were identified. Mean LA-MACSA and LA-AP were significantly larger in patients with AFib than in patients without AFib (28.63 vs. 20.53 cm2, P<0.000001; 4.34 vs. 3.5 cm, P<0.000001, respectively), both with area under the curves (AUCs) of 0.73. Multivariable logistic regression analysis including age, sex, and VB-Area with LA-MACSA improved the AUC for predicting AFib (AUC=0.77). An LA-MACSA threshold of 30 cm2 demonstrated high specificity for AFib diagnosis at 92% and sensitivity of 48%, and LA-AP threshold at 4.5 cm demonstrated 90% specificity and 42% sensitivity. A Bayesian machine learning model using age, sex, height, body surface area, and LA-MACSA predicted AFib with an AUC of 0.743. Conclusions: LA-MACSA or LA-AP can be rapidly measured from routine chest CT, and when >30 cm2 and >4.5 cm, respectively, are specific indicators to predict patients at increased risk for AFib.