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1. CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis

   https://doi.org/10.1097/MPG.0000000000002480  

   Mougey, Edward B. ; Williams, Andre ; Coyne, Ashlan J. Kunz ; Gutiérrez‐Junquera, Carolina ; Fernández‐Fernández, Sonia ; Cilleruelo, Maria Luz ; Rayo, Ana ; Echeverría, Luis ; Román, Enriqueta ; González Lois, Carmen ; et al ( November 2019 , Journal of Pediatric Gastroenterology and Nutrition)

   Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants inCYP2C19andSTAT6associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes forCYP2C19andSTAT6influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI‐REE, PPI‐nonresponsive EoE).

   Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high‐dose PPI therapy for esophageal eosinophilia in children.

   Of the 92 patients examined, 57 (62%) were PPI‐REE and 35 (38%) were PPI‐nonresponsive EoE. Forty‐six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage ofCYP2C19^*17(P= 0.35). In children who received a PPI dose between ≥1.54 and ⩽2.05 mg/kg/day, binary logistic regression modeling showed that carriage ofCYP2C19^*17associated with PPI‐nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11],P= 0.031). Carriage ofSTAT6allelic variant rs1059513 predicts PPI‐REE (OR [95% CI] = 6.16 [1.44, 26.4],P= 0.028), whereas carriage ofSTAT6rs324011 synergizes withCYP2C19^*17to predict PPI‐nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72],P= 0.022;CYP2C19^*17OR [95% CI] = 8.19[1.42, 50.57],P= 0.023).

   Common variants inCYP2C19andSTAT6associate with a PPI‐nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype‐guided approach to PPI dosing.

    

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2. Real‐world experience using hydroxyurea in children with sickle cell disease in Lilongwe, Malawi

   https://doi.org/10.1002/pbc.27954  

   Mvalo, Tisungane ; Topazian, Hillary M. ; Kamthunzi, Portia ; Chen, Jane S. ; Kambalame, Isobel ; Mafunga, Pilirani ; Mumba, Noel ; Chiume, Msandeni ; Paseli, Khadija ; Tegha, Gerald ; et al ( August 2019 , Pediatric Blood & Cancer)

   Sickle cell disease (SCD) is among the most common inherited hematologic diseases in sub‐Saharan Africa (SSA). Historically, hydroxyurea administration in SSA has been restricted due to limited region‐specific evidence for safety and efficacy.

   We conducted a prospective observational cohort study of pediatric patients with SCD in Malawi. From January 2015 to November 2017, hydroxyurea at doses of 10–20 mg/kg/day was administered to children with clinically severe disease (targeted use policy). From December 2017 to July 2018, hydroxyurea was prescribed to all patients (universal use policy).

   Of 187 patients with SCD, seven (3.7%) died and 23 (12.3%) were lost to follow‐up. The majority (135, 72.2%) were prescribed hydroxyurea, 59 (43.7%) under the targeted use policy and 76 (56.3%) under the universal use policy. There were no documented severe toxicities. Under the targeted use policy, children with SCD demonstrated absolute decreases in the rates of hospitalization (−4.1 per 1000 person‐days; −7.2, −1.0;P = .004), fevers (−4.2 per 1000 person‐days; −7.2, −1.1;P = .002), transfusions (−2.3 per 1000 person‐days; 95% confidence interval: −4.9, 0.3;P = .06), and annual school absenteeism (−51.2 per person‐year; −60.1, −42.3;P < .0001) within 6 months of hydroxyurea commencement.

   We successfully implemented universal administration of hydroxyurea to children with SCD at a tertiary hospital in Malawi. Similar to recently reported trials, hydroxyurea was safe and effective during routine programmatic experience, with clinical benefits particularly among high‐risk children. This highlights the importance of continued widespread scale‐up of hydroxyurea within SCD programs across SSA.

    

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3. Alpha to Omicron: Disease Severity and Clinical Outcomes of Major SARS-CoV-2 Variants

   https://doi.org/10.1093/infdis/jiac411  

   Esper, Frank P. ; Adhikari, Thamali M. ; Tu, Zheng Jin ; Cheng, Yu-Wei ; El-Haddad, Kim ; Farkas, Daniel H. ; Bosler, David ; Rhoads, Daniel ; Procop, Gary W. ; Ko, Jennifer S. ; et al ( October 2022 , The Journal of Infectious Diseases)

   Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants remains limited.

   Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes.

   In total 2779 patients identified with either Alpha (n = 1153), Gamma (n = 122), Delta (n = 808), or Omicron variants (n = 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (χ2 = 12.8, P < .001; χ2 = 21.6, P < .002; χ2 = 9.6, P = .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 [26.9%] and 513/696 [73.7%], respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2.

   Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.

    

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4. Whole blood transcriptomics identifies subclasses of pediatric septic shock

   https://doi.org/10.1186/s13054-023-04689-y  

   Yang, Jamie O. ; Zinter, Matt S. ; Pellegrini, Matteo ; Wong, Man Yee ; Gala, Kinisha ; Markovic, Daniela ; Nadel, Brian ; Peng, Kerui ; Do, Nguyen ; Mangul, Serghei ; et al ( December 2023 , Critical Care)

   Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.

   The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.

   Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.

   Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.

   Trial RegistrationThis is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

    

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5. Acute phase response to exertional heat stroke in mice

   https://doi.org/10.1113/EP088501  

   Iwaniec, John ; Robinson, Gerard P. ; Garcia, Christian K. ; Murray, Kevin O. ; de Carvalho, Lucas ; Clanton, Thomas L. ; Laitano, Orlando ( May 2020 , Experimental Physiology)

   What is the central question of this study?

   Exertional heat stroke is accompanied by a marked inflammatory response. In this study, we explored the time course of acute phase proteins during recovery from severe heat stress in mice and the potential role of skeletal muscles as their source.

   What is the main finding and its importance?

   Exertional heat stroke transiently increased expression of acute phase proteins in mouse liver and plasma and depleted liver and plasma fibrinogen, a typical response to severe trauma. In contrast, skeletal muscle fibrinogen production was stimulated by heat stroke, which can provide an additional reservoir for fibrinogen supply to maintain the clotting potential throughout the body and locally within the muscle.

   Exertional heat stroke (EHS), the most severe manifestation of heat illness, is accompanied by a marked inflammatory response. The release of acute phase proteins (APPs) is an important component of inflammation, which can assist in tissue survival/repair. The time course of APPs in recovery from EHS is unknown. Furthermore, skeletal muscles produce APPs during infection, but it is unknown whether they can produce APPs after EHS. Our objective was to determine the time course of representative APPs in liver, plasma and skeletal muscle during recovery from EHS. Male C57BL6/J mice ran in a forced running wheel at 37.5°C, 40% relative humidity until symptom limitation. Exercise control (EXC) mice ran for the same duration and intensity at 22.5°C. Samples were collected (n = 6–12 per group) over 14 days of recovery. Protein abundance was quantified using immunoblots. Total and phosphorylated STAT3 (pSTAT3) at Tyr705, responsible for APP activation, increased in liver at 0.5 h after EHS compared with EXC, (P < 0.05 andP < 0.001, respectively). In contrast, in tibialis anterior (TA) muscle, total STAT3 increased at 3 h (P < 0.05) but pSTAT3 (Tyr705) did not. Liver serum amyloid A1 (SAA1) increased at 3 and 24 h after EHS (P < 0.05), whereas plasma SAA1 increased only at 3 h (P < 0.05). SAA1 was not detected in TA muscle. In liver and plasma, fibrinogen decreased at 3 h (P < 0.01) and increased in TA muscle (P < 0.05). Lipocalin‐2 was undetectable in liver or TA muscle. Recovery from EHS is characterized by a transient acute phase response in both liver and skeletal muscle. However, APP expression profiles and subtypes differ between skeletal muscle and liver.

    

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