Clinical Course, Nosocomial, and Opportunistic Infections Among Kidney Transplant Recipients with COVID-19: A Retrospective Single Center Study.

BACKGROUND: We report the results of an observational study, analyzing the clinical course of kidney transplant patients hospitalized for COVID-19 and comparing it with a control to determine if outcomes, nosocomial, and opportunistic infections were different between groups. METHODS: An observational, retrospective, case-control, single-center study, including a group of kidney transplant adults diagnosed with COVID-19, from March 2020 to April 2022. Transplant patients hospitalized for COVID-19 comprised the cases. The control group consisted of non-transplanted adults, without immunosuppressive treatment, hospitalized for COVID-19, and matched by age, sex, and month at diagnosis of COVID-19. Study variables were collected, including demographic/clinical, epidemiologic, clinical/biological at diagnosis, evolutive, and outcome variables. RESULTS: Fifty-eight kidney transplant recipients were included. Thirty required hospital admission. Ninety controls were included. Transplant recipients had a higher frequency of intensive care unit (ICU) admission, ventilatory support, and death. The relative risk for death was 2.45. When adjusted by baseline estimated glomerular filtration rate (eGFR) and comorbidity, only the risk for opportunistic infection remained high. Variables independently associated with death were dyslipidemia, eGFR at admission, MULBSTA score, and ventilatory support. Pneumonia by Klebsiella oxytoca was the most frequent nosocomial infection. Pulmonary aspergillosis was the most frequent opportunistic infection overall. Pneumocystosis and cytomegalovirus colitis were more frequent among transplant patients. The relative risk for opportunistic infection in this group was 1.88. Baseline eGFR, serum interleukin 6 level, and coinfection were independently associated with it. CONCLUSIONS: Evolutive course of COVID-19 requiring hospitalization in renal transplant recipients was primarily determined by comorbidity and baseline kidney function. At equal comorbidity and renal function, there were no differences in mortality, ICU admission, nosocomial infection, and hospital stay. However, the risk for opportunistic infection remained high.

JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States.

Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC. SIGNIFICANCE: Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.

Ultrasound Predicts White Matter Integrity after Hypothermia Therapy in Neonatal Hypoxic-Ischemic Injury.

BACKGROUND: Hypoxic-ischemic injury (HII) is a major cause of neonatal death and neurodevelopmental disability. Head ultrasounds (HUS) in neonates with HII often show enhanced gray/white matter differentiation. We assessed the significance of this finding in predicting white matter structural integrity measured by diffusion tensor imaging (DTI) in neonates with HII. METHODS: We performed a quantitative region of interest-based analysis of white and gray matter echogenicity within the cingulate gyrus on pre- and posthypothermia HUS. We also completed a quantitative analysis of fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity within the bilateral anterior and posterior centrum semiovale (CSO) on posthypothermia brain magnetic resonance imaging. For HUS studies, we calculated a white-to-gray matter echogenicity ratio (WGR) and subsequently correlated it to DTI measurements. RESULTS: Forty-two term neonates with HII who underwent hypothermia therapy were included. Significant correlation was found between prehypothermia WGR and MD, AD, and RD values in the left anterior CSO (r = .38-.40, P = .02). Prehypothermia WGR also correlated with the following: MD and RD in the right anterior CSO (r = .35-.36, P = .04), MD and AD in the right posterior CSO (r = .32-.45, P = .008-.03), and AD in the left posterior CSO (r = .47, P = .005). No significant correlation was found either between prehypothermia WGR and FA values in the bilateral anterior and posterior CSO or between posthypothermia WGR and all DTI scalars in the bilateral anterior and posterior CSO. CONCLUSIONS: Prehypothermia HUS WGR may predict posthypothermia white matter structural integrity and is potentially an early and easily obtainable biomarker of severity in neonatal HII.

The Role of Diffusion Tensor Imaging in Detecting Hippocampal Injury Following Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND AND PURPOSE: Neonatal hypoxic-ischemic injury of the brain and resultant encephalopathy (HIE) leads to major developmental impairments by school age. Conventional/anatomical MRI often fails to detect hippocampal injury in mild cases. We hypothesize that diffusion tensor imaging (DTI) has greater sensitivity for identifying subtle hippocampal injury. METHODS: We retrospectively analyzed DTI data collected from a cohort of neonates with HIE and controls. Conventional MRI sequences were classified qualitatively according to severity using a modified Barkovich scale. Using multivariate linear regression, we compared hippocampal DTI scalars of HIE patients and controls. Spearman correlation was used to test the association of DTI scalars in the hippocampal and thalamic regions. A multiple regression analysis tested the association of the DTI scalars with short-term outcomes. RESULTS: Fifty-five neonates with HIE (42% males) and 13 controls (54% males) were included. Hippocampal DTI scalars were similar between HIE and control groups, even when restricting the HIE group to those with moderate-to-severe injury (8 subjects). DTI scalars of the thalamus were significantly lower in the moderate-to-severely affected patients compared to controls (right fractional anisotropy [FA] .148 vs. .182, P = .01; left FA .147 vs. .181, P = .03). Hippocampal and thalamic DTI scalars were correlated (P < .001). Hippocampal DTI scalars were not associated with short-term outcomes. CONCLUSIONS: Quantitative DTI analysis of the hippocampus in neonates following HIE is a feasible technique to examine neuronal injury. Although DTI scalars were useful in identifying thalamic injury in our cohort, hippocampal DTI analysis did not provide additional information regarding hippocampal injury following HIE.

Severe Neonatal Manifestations of Infantile Liver Failure Syndrome Type 1 Caused by Cytosolic Leucine-tRNA Synthetase Deficiency.

BACKGROUND: Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented. CASE REPORT: We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient. CONCLUSION: This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.

Head Ultrasound in Neonatal Hypoxic-Ischemic Injury and Its Mimickers for Clinicians: A Review of the Patterns of Injury and the Evolution of Findings Over Time.

Hypoxic-ischemic injury (HII) of the neonatal brain and resulting clinical hypoxic-ischemic encephalopathy remains a significant cause of morbidity and mortality in the neonatal population. Ultrasound (US) has emerged as a powerful screening tool for evaluation of a neonate with suspected HII. The pattern of injury on brain imaging has crucial implications in therapies and predicted neurodevelopmental outcomes. US has become increasingly effective at determining the pattern, timing, and extent of injury in HII as well as differentiating these findings from a host of diagnoses that can result in a similarly appearing clinical picture. Repeated US studies over a patient's course can define the evolution of findings from the acute through chronic phase in addition to identifying any complications of therapy. US also has the added benefits of easy portability, no need for patient sedation, and a relatively low cost when compared to other imaging modalities like magnetic resonance imaging (MRI). It is crucial that clinicians understand the full capabilities of advanced US in identifying an underlying diagnosis, directing appropriate therapy, monitoring disease progress, and finally in predicting outcomes, thus improving the care of neonates with encephalopathy. The following article demonstrates the breadth of uses for US in the full-term neonate with encephalopathy, its limitations, the patterns of injury seen, and their evolution over time. We will also briefly review several clinical mimickers of HII for comparison.