Lorentsencardenas3005

Picornaviruses, including Enterovirus species A to D (EV) and Parechovirus species A (PeV-A), are the leading reported causes of pediatric central nervous system infections in the United States. We investigated the molecular epidemiology of EV and PeV-A over 10 years in cerebrospinal fluid (CSF) collected from children seen at Children's Mercy-Kansas City (CMKC) from 2007 through 2016. The overall prevalence for EV was 16% (862/5,362) and 7% (271/4,016) for PeV. Among all picornavirus CSF detections, EV was 76%, and PeV-A was 24%. Multiple EV types cocirculated each year, with a total of 31 EV types detected in the 10-year period; the majority belonged to EV-B species (96%). Two PeV-A types were detected; PeV-A3 was the dominant PeV-A type (95%). The top five picornaviruses (PeV-A3, 26%; E30, 11%; E6, 10%; E18, 9%; E9, 7%) in the CSF of infants accounted for two-thirds of all detections, and PeV-A3 was the leading picornavirus detected. Routine testing and reporting of PeV-A in addition to EV, especially in children under 6 months old with acute febrile illnesses, could reduce hospital stays and antibiotic usage.Accurate and early susceptibility results could reduce overuse of broad-spectrum antibiotics for empirical treatment of bacteremia. Direct disk diffusion testing (dDD) using nonstandardized inocula directly from blood cultures could facilitate earlier narrowing of antibiotics. To determine the predictive value of dDD compared with standardized antimicrobial susceptibility testing (AST), we performed a retrospective cohort study of 582 blood cultures from 495 pediatric patients with bacteremia. Positive and negative predictive value (PPV number of isolates susceptible by both dDD and AST divided by the total number of isolates susceptible by dDD; NPV number of isolates not susceptible [either intermediate or resistant] by both dDD and AST divided by the total number of isolates not susceptible by dDD), sensitivity, specificity, and 95% confidence interval were calculated for each bacterium-antibiotic combination. We evaluated the Antibiotic Spectrum Index of prescribed antibiotics to assess change in antibiotic prescribing after availability of Gram stain, dDD, and AST results. dDD results were available a median of 21 h before AST results. dDD had PPVs of ≥96% for most organism-antibiotic pairs, including 100% (CI 96 to 100%) for Staphylococcus aureus with oxacillin and 99% (CI 93 to 100%) for Enterobacterales with ceftriaxone. NPVs of dDD were variable and frequently lower than the PPV. Very major errors and major errors occurred in 31/5,454 (0.6%) and 231/5,454 (4.2%) organism-antibiotic combinations, respectively. Antibiotics were narrowed in 30% of cases after a dDD result and a further 25% of cases after AST result. dDD is highly predictive of susceptibility for many common organism-antibiotic combinations and provides actionable information one day earlier than standard susceptibility approaches. dDD has the potential to facilitate earlier deescalation to narrow-spectrum antibiotic treatment.In Spain, PCR is the tool of choice for the diagnosis of congenital Chagas disease (CD) and serology for diagnosing chronic CD. A loop-mediated isothermal amplification test for Trypanosoma cruzi DNA detection showed good analytical performance and ease of use. We aimed to evaluate the performance of the Loopamp Trypanosoma cruzi detection kit (Eiken Chemical Co. Ltd., Japan) (Tcruzi-LAMP) for congenital and chronic CD diagnosis using well-characterized samples. We included samples from 39 congenital and 174 chronic CD cases and from 48 uninfected children born to infected mothers and 34 nonchagasic individuals. The sensitivity, specificity, and accuracy of Tcruzi-LAMP were estimated using standard case definitions for congenital CD (positive result by parasitological or PCR tests or serology after 9 months of age) and chronic CD (positive serology by at least two tests). The Tcruzi-LAMP results were read by visual examination and a real-time fluorimeter. For congenital CD, Tcruzi-LAMP sensitivity was 97% for both types of reading; specificity was 92% by visual examination and 94% by fluorimeter. For chronic CD, sensitivity was 47% and specificity 100%. The accuracy in congenital CD was >94% versus 56% in chronic CD. The agreement of Tcruzi-LAMP with PCR tests was better in congenital CD (kappa, 0.86 to 0.91) than in chronic CD (kappa, 0.67 to 0.83). The Loopamp Trypanosoma cruzi detection kit showed good performance for the diagnosis of congenital CD. Tcruzi-LAMP, like PCR, can be useful for the screening and early diagnosis of congenital infection.Colombia, South America has one of the world's highest burdens of Helicobacter pylori infection and gastric cancer. While multidrug antibiotic regimens can effectively eradicate H. pylori, treatment efficacy is being jeopardized by the emergence of antibiotic-resistant H. pylori strains. Moreover, the spectrum of and genetic mechanisms for antibiotic resistance in Colombia is underreported. In this study, 28 H. pylori strains isolated from gastric biopsy specimens from a high-gastric-cancer-risk (HGCR) population living in the Andes Mountains in Túquerres, Colombia and 31 strains from a low-gastric-cancer-risk (LGCR) population residing on the Pacific coast in Tumaco, Colombia were subjected to antibiotic susceptibility testing for amoxicillin, clarithromycin, levofloxacin, metronidazole, rifampin, and tetracycline. Resistance-associated genes were amplified by PCR for all isolates, and 29 isolates were whole-genome sequenced (WGS). No strains were resistant to amoxicillin, clarithromycin, or rifampin. One strain was resistant to tetracycline and had an A926G mutation in its 16S rRNA gene. Levofloxacin resistance was observed in 12/59 isolates and was significantly associated with N87I/K and/or D91G/Y mutations in gyrA Most isolates were resistant to metronidazole; this resistance was significantly higher in the LGCR (31/31) group compared to the HGCR (24/28) group. Truncations in rdxA and frxA were present in nearly all metronidazole-resistant strains. There was no association between phylogenetic relationship and resistance profiles based on WGS analysis. Our results indicate H. pylori isolates from Colombians exhibit multidrug antibiotic resistance. Continued surveillance of H. pylori antibiotic resistance in Colombia is warranted in order to establish appropriate eradication treatment regimens for this population.The therapeutic goal for autoimmune diseases is disease antigen-specific immune tolerance without nonspecific immune suppression. However, it is a challenge to induce antigen-specific immune tolerance in a dysregulated immune system. In this study, we developed immune-homeostatic microparticles (IHMs) that treat multiple mouse models of autoimmunity via induction of apoptosis in activated T cells and reestablishment of regulatory T cells. Specifically, in an experimental model of colitis, IHMs rapidly released monocyte chemotactic protein-1 after intravenous administration, which recruited activated T cells and then induced their apoptosis by conjugated Fas ligand on the IHM surface. This triggered professional macrophages to ingest apoptotic T cells and produce high quantities of transforming growth factor-β, which drove regulatory T cell differentiation. Furthermore, the modular design of IHMs allowed IHMs to be engineered with the autoantigen peptides that can reduce disease in an experimental autoimmune encephalomyelitis mouse model and a nonobese diabetic mouse model. This was accomplished by sustained release of the autoantigens after induction of T cell apoptosis and transforming growth factor-β production by macrophages, which promoted to establish an immune tolerant environment. Thus, IHMs may be an efficient therapeutic strategy for autoimmune diseases through induction of apoptosis and reestablishment of tolerant immune responses.Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.The COVID-19 pandemic halted research operations at academic medical centers. This shutdown has adversely affected research infrastructure, the current research workforce, and the research pipeline. see more We discuss the impact of the pandemic on overall research operations, examine its disproportionate effect on underrepresented minority researchers, and provide concrete strategies to reverse these losses.Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.