Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of Ab responses to T cell-independent type 2 pneumococcal capsular polysaccharides (PPS). The pneumococcal polysaccharide-protein conjugate vaccine-13 (PCV-13) contains PPS conjugated to the T cell-dependent protein (diphtheria toxoid [DT] [CRM197]). We investigated the differential response to PPS and DT by human Ab-secreting B cells (ASC) after immunization with PCV-13 in newly diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls. However, DT-specific IgG ASC increased in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (Tfh) cells, the predominant T cell subset providing B cell help. Expression of inducible T cell costimulator (ICOS), which sustains Tfh function and phenotype, increased significantly among controls, when compared with the HIV+ group. Increases in ICOS+ Tfh correlated with changes in T-dependent, DT-specific IgG ASC in controls but not in HIV+ In contrast, ICOS expression did not correlate with T cell-independent type 2 PPS-specific ASC in either group. Of note, upon optimized ex vivo stimulation, CD4 T cells from HIV+ subjects differentiated into Tfh cells and formed synapses with Raji B cells at frequencies similar to that of controls. In summary, PCV-13-induced increase in ICOS expression on Tfh was associated with responses to DT, which was compromised in recently diagnosed healthy HIV+ adults and can be restored ex vivo by providing effective Tfh-differentiating signals.The costimulatory receptor CD28 synergizes with the TCR to promote IL-2 production, cell survival, and proliferation; yet the obligatory interdependence of TCR and CD28 signaling is not well understood. Upon TCR stimulation, Gads, a Grb2-family adaptor, bridges the interaction of two additional adaptors, LAT and SLP-76, to form a TCR-induced effector signaling complex. SLP-76 binds the Tec-family tyrosine kinase, Itk, which phosphorylates SLP-76 Y173 and PLC-γ1 Y783. In this study, we identified TCR-inducible, Itk-mediated phosphorylation of Gads Y45 in a human T cell line and in mouse primary T cells. Y45 is found within the N-terminal SH3 domain of Gads, an evolutionarily conserved domain with no known signaling function. Gads Y45 phosphorylation depended on the interaction of Gads with SLP-76 and on the dimerization-dependent binding of Gads to phospho-LAT. We provide evidence that Itk acts through SLP-76 and Gads to promote the TCR/CD28-induced activation of the RE/AP transcriptional element from the IL-2 promoter. Two Itk-related features of SLP-76, Y173 and a proline-rich Itk SH3 binding motif on SLP-76, were dispensable for activation of NFAT but selectively required for the TCR/CD28-induced increase in cytoplasmic and nuclear c-Rel and consequent RE/AP activation. We provide evidence that unphosphorylated, monomeric Gads mediates an RE/AP-directed inhibitory activity that is mitigated upon Gads dimerization and Y45 phosphorylation. This study illuminates a new, to our knowledge, regulatory module, in which TCR-induced, Itk-mediated phosphorylation sites on SLP-76 and Gads control the transcriptional response to TCR/CD28 costimulation, thus enforcing the obligatory interdependence of the TCR and CD28 signaling pathways.Persistence of a left-to-right shunt caused by a patent ductus arteriosus (PDA) leads to significant sequelae in extremely premature infants as a result of pulmonary overcirculation and systemic steal. Although timing and duration of treatment for a persistent clinically significant PDA differ among institutions, standard pharmacologic interventions are the nonsteroidal anti-inflammatory drugs indomethacin and ibuprofen. Acetaminophen has emerged as an alternative to indomethacin and ibuprofen with less significant adverse effects, but there is no consensus regarding its use. This review summarizes the most recent evidence for the use of acetaminophen in PDA treatment.Tremendous advances have been made in the last 5 decades in the surgical management of congenital heart disease (CHD). Most infants affected by clinically significant CHD are at risk for developing heart failure (HF). this website Adult HF management is mostly evidence-based and our knowledge in this field has expanded significantly in the past decade. However, data on management approaches for HF in infants are limited. The indications and implications for various medications and interventions in patients with HF secondary to CHD are an upcoming area of interest. It is critical that we expand our ability to prevent, detect, and manage HF in the pediatric population.Primary pulmonary vein stenosis (PPVS) represents a rare but emerging, often progressive heterogeneous disease with high morbidity and mortality in the pediatric population. Although our understanding of PPVS disease has improved markedly in recent years, much remains unknown regarding disease pathogenesis, distinct disease phenotypes, and patient- and disease-related risk factors driving the unrelenting disease progression characteristic of PPVS. In the pediatric population, risk factors identified in the development of PPVS include an underlying congenital heart disease, prematurity and associated conditions, and an underlying genetic or congenital syndrome. Continued improvement in the survival of high-risk populations, coupled with ongoing advances in general PPVS awareness and diagnostic imaging technologies suggest that PPVS will be an increasingly prevalent disease affecting pediatric populations in the years to come. However, significant challenges persist in both the diagnosis and management of PPVS. Standardized definitions and risk stratification for PPVS are lacking. Furthermore, evidence-based guidelines for screening, monitoring, and treatment remain to be established. Given these limitations, significant practice variation in management approaches has emerged across centers, and contemporary outcomes for patients affected by PPVS remain guarded. To improve care and outcomes for PPVS patients, the development and implementation of universal definitions for disease and severity, as well as evidence-based guidelines for screening, monitoring, cardiorespiratory care, and indications for surgical intervention will be critical. In addition, collaboration across institutions will be paramount in the creation of regionalized referral centers as well as a comprehensive patient registry for those requiring pulmonary vein stenosis.