Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies

Markers of Inflammation in Bacterial Diarrhea among Travelers, with a Focus on Enteroaggregative Escherichia coli Pathogenicity

The intestinal inflammatory response of traveler's diarrhea acquired in Goa, India, and Guadalajara, Mexico, was studied. Fecal lactoferrin was found in stool samples in which enteroaggregative Escherichia coli (EAEC), enterotoxigenic E. coli, or Salmonella or Shigella species were isolated, with Shigella-positive cases showing the highest level. Samples from cases of Shigella-associated diarrhea had the highest concentrations of fecal cytokines. Travelers to India who had EAEC-associated diarrhea showed elevated levels of interleukin (IL)-8 (median, 341.15 pg/mL) and IL-1β (median, 749.90 pg/mL). Although 15 travelers to Mexico who had EAEC-associated diarrhea had a median concentration of 0 pg/mL for both IL-8 and IL-1β, 2 had high levels of IL-8 (1853 and 11,786 pg/mL), and 5 showed elevated levels of IL-1β (1-1240 pg/mL). Samples from patients in India who had pathogen-negative diarrhea or from patients in Mexico who had asymptomatic EAEC infection were negative for cytokines. Bacterial pathogens causing traveler's diarrhea commonly produce intestinal inflammation, although a subset of patients with EAEC-associated diarrhea fail to develop an inflammatory respons

Rigidity of limit sets for nonplanar geometrically finite Kleinian groups of the second kind

We consider the relation between geometrically finite groups and their limit sets in infinite-dimensional hyperbolic space. Specifically, we show that a rigidity theorem of Susskind and Swarup ('92) generalizes to infinite dimensions, while a stronger rigidity theorem of Yang and Jiang ('10) does not

Translating data analytics into improved spine surgery outcomes: A roadmap for biomedical informatics research in 2021

STUDY DESIGN: Narrative review. OBJECTIVES: There is growing interest in the use of biomedical informatics and data analytics tools in spine surgery. Yet despite the rapid growth in research on these topics, few analytic tools have been implemented in routine spine practice. The purpose of this review is to provide a health information technology (HIT) roadmap to help translate data assets and analytics tools into measurable advances in spine surgical care. METHODS: We conducted a narrative review of PubMed and Google Scholar to identify publications discussing data assets, analytical approaches, and implementation strategies relevant to spine surgery practice. RESULTS: A variety of data assets are available for spine research, ranging from commonly used datasets, such as administrative billing data, to emerging resources, such as mobile health and biobanks. Both regression and machine learning techniques are valuable for analyzing these assets, and researchers should recognize the particular strengths and weaknesses of each approach. Few studies have focused on the implementation of HIT, and a variety of methods exist to help translate analytic tools into clinically useful interventions. Finally, a number of HIT-related challenges must be recognized and addressed, including stakeholder acceptance, regulatory oversight, and ethical considerations. CONCLUSIONS: Biomedical informatics has the potential to support the development of new HIT that can improve spine surgery quality and outcomes. By understanding the development life-cycle that includes identifying an appropriate data asset, selecting an analytic approach, and leveraging an effective implementation strategy, spine researchers can translate this potential into measurable advances in patient care

Stringent Limits on the Polarized Submillimeter Emission from Protoplanetary Disks

We present arcsecond-resolution Submillimeter Array (SMA) polarimetric observations of the 880 um continuum emission from the protoplanetary disks around two nearby stars, HD 163296 and TW Hydrae. Although previous observations and theoretical work have suggested that a 2-3% polarization fraction should be common for the millimeter continuum emission from such disks, we detect no polarized continuum emission above a 3-sigma upper limit of 7 mJy in each arcsecond-scale beam, or <1% in integrated continuum emission. We compare the SMA upper limits with the predictions from the exploratory Cho & Lazarian (2007) model of polarized emission from T Tauri disks threaded by toroidal magnetic fields, and rule out their fiducial model at the ~10-sigma level. We explore some potential causes for this discrepancy, focusing on model parameters that describe the shape, magnetic field alignment, and size distribution of grains in the disk. We also investigate related effects like the magnetic field strength and geometry, scattering off of large grains, and the efficiency of grain alignment, including recent advances in grain alignment theory, which are not considered in the fiducial model. We discuss the impact each parameter would have on the data and determine that the suppression of polarized emission plausibly arises from rounding of large grains, reduced efficiency of grain alignment with the magnetic field, and/or some degree of magnetic field tangling (perhaps due to turbulence). A poloidal magnetic field geometry could also reduce the polarization signal, particularly for a face-on viewing geometry like the TW Hya disk. The data provided here offer the most stringent limits to date on the polarized millimeter-wavelength emission from disks around young stars.Comment: 15 pages, 6 figures, accepted for publication in Ap

Applications of patching to quadratic forms and central simple algebras

This paper provides applications of patching to quadratic forms and central simple algebras over function fields of curves over henselian valued fields. In particular, we use a patching approach to reprove and generalize a recent result of Parimala and Suresh on the u-invariant of p-adic function fields, for p odd. The strategy relies on a local-global principle for homogeneous spaces for rational algebraic groups, combined with local computations.Comment: 48 pages; connectivity now required in the definition of rational group; beginning of Section 4 reorganized; other minor change