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We report on the implications for cosmic inflation of the 2018 release of the Planck cosmic microwave background (CMB) anisotropy measurements. The results are fully consistent with those reported using the data from the two previous Planck cosmological releases, but have smaller uncertainties thanks to improvements in the characterization of polarization at low and high multipoles. Planck temperature, polarization, and lensing data determine the spectral index of scalar perturbations to be ns = 0.9649 ± 0.0042 at 68% CL. We find no evidence for a scale dependence of ns, either as a running or as a running of the running. The Universe is found to be consistent with spatial flatness with a precision of 0.4% at 95% CL by combining Planck with a compilation of baryon acoustic oscillation data. The Planck 95% CL upper limit on the tensor-to-scalar ratio, r0.002 < 0.10, is further tightened by combining with the BICEP2/Keck Array BK15 data to obtain r0.002 < 0.056. In the framework of standard single-field inflationary models with Einstein gravity, these results imply that: (a) the predictions of slow-roll models with a concave potential, V″(φ) < 0, are increasingly favoured by the data; and (b) based on two different methods for reconstructing the inflaton potential, we find no evidence for dynamics beyond slow roll. Three different methods for the non-parametric reconstruction of the primordial power spectrum consistently confirm a pure power law in the range of comoving scales 0.005 Mpc-1 k 0.2 Mpc-1. A complementary analysis also finds no evidence for theoretically motivated parameterized features in the Planck power spectra. For the case of oscillatory features that are logarithmic or linear in k, this result is further strengthened by a new combined analysis including the Planck bispectrum data. The new Planck polarization data provide a stringent test of the adiabaticity of the initial conditions for the cosmological fluctuations. In correlated, mixed adiabatic and isocurvature models, the non-adiabatic contribution to the observed CMB temperature variance is constrained to 1.3%, 1.7%, and 1.7% at 95% CL for cold dark matter, neutrino density, and neutrino velocity, respectively. Planck power spectra plus lensing set constraints on the amplitude of compensated cold dark matter-baryon isocurvature perturbations that are consistent with current complementary measurements. The polarization data also provide improved constraints on inflationary models that predict a small statistically anisotropic quadupolar modulation of the primordial fluctuations. However, the polarization data do not support physical models for a scale-dependent dipolar modulation. All these findings support the key predictions of the standard single-field inflationary models, which will be further tested by future cosmological observations.

We report on the implications for cosmic inflation of the 2018 release of the Planck cosmic microwave background (CMB) anisotropy measurements. The results are fully consistent with those reported using the data from the two previous Planck cosmological releases, but have smaller uncertainties thanks to improvements in the characterization of polarization at low and high multipoles. Planck temperature, polarization, and lensing data determine the spectral index of scalar perturbations to be ns = 0.9649 ± 0.0042 at 68% CL. We find no evidence for a scale dependence of ns, either as a running or as a running of the running. The Universe is found to be consistent with spatial flatness with a precision of 0.4% at 95% CL by combining Planck with a compilation of baryon acoustic oscillation data. The Planck 95% CL upper limit on the tensor-to-scalar ratio, r0.002 < 0.10, is further tightened by combining with the BICEP2/Keck Array BK15 data to obtain r0.002 < 0.056. In the framework of standard single-field inflationary models with Einstein gravity, these results imply that: (a) the predictions of slow-roll models with a concave potential, V″(φ) < 0, are increasingly favoured by the data; and (b) based on two different methods for reconstructing the inflaton potential, we find no evidence for dynamics beyond slow roll. Three different methods for the non-parametric reconstruction of the primordial power spectrum consistently confirm a pure power law in the range of comoving scales 0.005 Mpc-1 k 0.2 Mpc-1. A complementary analysis also finds no evidence for theoretically motivated parameterized features in the Planck power spectra. For the case of oscillatory features that are logarithmic or linear in k, this result is further strengthened by a new combined analysis including the Planck bispectrum data. The new Planck polarization data provide a stringent test of the adiabaticity of the initial conditions for the cosmological fluctuations. In correlated, mixed adiabatic and isocurvature models, the non-adiabatic contribution to the observed CMB temperature variance is constrained to 1.3%, 1.7%, and 1.7% at 95% CL for cold dark matter, neutrino density, and neutrino velocity, respectively. Planck power spectra plus lensing set constraints on the amplitude of compensated cold dark matter-baryon isocurvature perturbations that are consistent with current complementary measurements. The polarization data also provide improved constraints on inflationary models that predict a small statistically anisotropic quadupolar modulation of the primordial fluctuations. However, the polarization data do not support physical models for a scale-dependent dipolar modulation. All these findings support the key predictions of the standard single-field inflationary models, which will be further tested by future cosmological observations.

Future observations of cosmic microwave background (CMB) polarisation have the potential to answer some of the most fundamental questions of modern physics and cosmology, including: what physical process gave birth to the Universe we see today? What are the dark matter and dark energy that seem to constitute 95% of the energy density of the Universe? Do we need extensions to the standard model of particle physics and fundamental interactions? Is the ΛCDM cosmological scenario correct, or are we missing an essential piece of the puzzle? In this paper, we list the requirements for a future CMB polarisation survey addressing these scientific objectives, and discuss the design drivers of the COREmfive space mission proposed to ESA in answer to the "M5" call for a medium-sized mission. The rationale and options, and the methodologies used to assess the mission's performance, are of interest to other future CMB mission design studies. COREmfive has 19 frequency channels, distributed over a broad frequency range, spanning the 60-600 GHz interval, to control astrophysical foreground emission. The angular resolution ranges from 2′ to 18′, and the aggregate CMB sensitivity is about 2 μKċarcmin. The observations are made with a single integrated focal-plane instrument, consisting of an array of 2100 cryogenically-cooled, linearly-polarised detectors at the focus of a 1.2-m aperture cross-Dragone telescope. The mission is designed to minimise all sources of systematic effects, which must be controlled so that no more than 10-4 of the intensity leaks into polarisation maps, and no more than about 1% of E-type polarisation leaks into B-type modes. COREmfive observes the sky from a large Lissajous orbit around the Sun-Earth L2 point on an orbit that offers stable observing conditions and avoids contamination from sidelobe pick-up of stray radiation originating from the Sun, Earth, and Moon. The entire sky is observed repeatedly during four years of continuous scanning, with a combination of three rotations of the spacecraft over different timescales. With about 50% of the sky covered every few days, this scan strategy provides the mitigation of systematic effects and the internal redundancy that are needed to convincingly extract the primordial B-mode signal on large angular scales, and check with adequate sensitivity the consistency of the observations in several independent data subsets. COREmfive is designed as a "near-ultimate" CMB polarisation mission which, for optimal complementarity with ground-based observations, will perform the observations that are known to be essential to CMB polarisation science and cannot be obtained by any other means than a dedicated space mission. It will provide well-characterised, highly-redundant multi-frequency observations of polarisation at all the scales where foreground emission and cosmic variance dominate the final uncertainty for obtaining precision CMB science, as well as 2′ angular resolution maps of high-frequency foreground emission in the 300-600 GHz frequency range, essential for complementarity with future ground-based observations with large telescopes that can observe the CMB with the same beamsize.

We forecast the main cosmological parameter constraints achievable with the CORE space mission which is dedicated to mapping the polarisation of the Cosmic Microwave Background (CMB). CORE was recently submitted in response to ESA's fifth call for medium-sized mission proposals (M5). Here we report the results from our pre-submission study of the impact of various instrumental options, in particular the telescope size and sensitivity level, and review the great, transformative potential of the mission as proposed. Specifically, we assess the impact on a broad range of fundamental parameters of our Universe as a function of the expected CMB characteristics, with other papers in the series focusing on controlling astrophysical and instrumental residual systematics. In this paper, we assume that only a few central CORE frequency channels are usable for our purpose, all others being devoted to the cleaning of astrophysical contaminants. On the theoretical side, we assume ΛCDM as our general framework and quantify the improvement provided by CORE over the current constraints from the Planck 2015 release. We also study the joint sensitivity of CORE and of future Baryon Acoustic Oscillation and Large Scale Structure experiments like DESI and Euclid. Specific constraints on the physics of inflation are presented in another paper of the series. In addition to the six parameters of the base ΛCDM, which describe the matter content of a spatially flat universe with adiabatic and scalar primordial fluctuations from inflation, we derive the precision achievable on parameters like those describing curvature, neutrino physics, extra light relics, primordial helium abundance, dark matter annihilation, recombination physics, variation of fundamental constants, dark energy, modified gravity, reionization and cosmic birefringence. In addition to assessing the improvement on the precision of individual parameters, we also forecast the post-CORE overall reduction of the allowed parameter space with figures of merit for various models increasing by as much as ∼ 107 as compared to Planck 2015, and 105 with respect to Planck 2015 + future BAO measurements.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed becau

Background: There is a trend toward linking the reimbursement for health care services to clinical outcome. One such pay-for-performance proposal that affects orthopaedic surgeons is linking reimbursement for hip and knee replacements to measures such as the percentage of patients receiving antibiotics before surgery. We analyzed the risk factors associated with failing to optimally administer preoperative antibiotics before primary hip and knee arthroplasty.Methods: Data on 988 elective primary total hip and knee replacements done at one institution were collected. Multivariate analysis was performed to determine clinical factors associated with administration of antibiotics outside the recommended window (within one hour before the incision).Results: Thirteen percent of the patients did not receive optimal antibiotic therapy (within the one-hour window prior to the elective arthroplasty). Five patients (0.5%) received no documented preoperative antibiotics. Patients undergoing total hip arthroplasty were more likely to receive antibiotics outside the one-hour window than were patients undergoing total knee arthroplasty. Longer induction times were associated with administration of antibiotics outside the one-hour window. Certain individual surgeons and anesthesiologists were more likely to administer antibiotics on time. The anesthesiologist effect was more significant than the surgeon effect.Conclusions: Approximately 13% of the patients did not receive optimal antibiotic therapy before total hip and knee replacement. Surgeons can improve their performance score for this measure by focusing antibiotic strategies on patients receiving a hip replacement and on complex cases, by developing systems for antibiotic dosing with the anesthesia team, and by improving documentation. [ABSTRACT FROM AUTHOR]

Objective: In this study, we evaluated the effectiveness of antimicrobial blue light (aBL; 410 nm wavelength) against β-lactamase-carrying bacteria and the effect of aBL on the activity of β-lactamases., Methods: Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae strains carrying β-lactamases as well as a purified β-lactamase enzymes were studied. β-lactamase activity was assessed using a chromogenic cephalosporin hydrolysis assay. Additionally, we evaluated the role of porphyrins in the photoreaction, as well as protein degradation by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Finally, we investigated the bactericidal effect of combined aBL-ceftazidime exposure against a metallo-β-lactamase expressing P. aeruginosa strain., Results: Our study demonstrated that aBL effectively killed β-lactamase-producing bacteria and reduced β-lactamase activity. After an aBL exposure of 1.52 J/cm 2 , a 50% reduction in enzymatic activity was observed in P. aeruginosa. Additionally, we found a 40% decrease in the photoreaction activity of porphyrins following an aBL exposure of 64.8 J/cm 2 . We also revealed that aBL reduced β-lactamase activity via protein degradation (after 136.4 J/cm 2 ). Additionally, aBL markedly improved the bactericidal effect of ceftazidime (by >4-log 10 ) in the metallo-β-lactamase P. aeruginosa strain., Conclusion: Our results provide evidence that aBL compromises bacterial β-lactamase activity, offering a potential approach to overcome β-lactam resistance in bacteria., (© 2024 Wiley Periodicals LLC.)

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2 + , triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

In this study, we showed that phenazine-1 carboxylic acid (PCA) of Pseudomonas aeruginosa induced the expression of Tet38 efflux pump triggering Staphylococcus aureus resistance to tetracycline and phenazines. Exposure of S. aureus RN6390 to supernatants of P. aeruginosa PA14 and its pyocyanin (PYO)-deficient mutants showed that P. aeruginosa non-PYO phenazines could induce the expression of Tet38 efflux pump. Direct exposure of RN6390 to PCA compound at 0.25× MIC led to a five-fold increase in tet38 transcripts. Expression of Tet38 protein was identified through confocal microscopy using RN6390(pRN- tet38 p- yfp ) that expressed YFP under control of the tet38 promoter by PCA at 0.25× MIC. The MICs of PCA of a Tet38-overexpressor and a Δtet38 mutant showed a three-fold increase and a two-fold decrease, respectively, compared with that of wild-type. Pre-exposure of RN6390 to PCA (0.25× MIC) for 1 hour prior to addition of tetracycline (1× or 10× MIC) improved bacteria viability of 1.5-fold and 2.6-fold, respectively, but addition of NaCl 7% together with tetracycline at 10× MIC reduced the number of viable PCA-exposed RN6390 of a 2.0-log 10 CFU/mL. The transcript levels of tetR21 , a repressor of tet38 , decreased and increased two-fold in the presence of PCA and NaCl, respectively, suggesting that the effects of PCA and NaCl on tet38 production occurred through TetR21 expression. These data suggest that PCA-induced Tet38 protects S. aureus against tetracycline during coinfection with P. aeruginosa ; however, induced tet38 -mediated S. aureus resistance to tetracycline is reversed by NaCl 7%, a nebulized treatment used to enhance sputum mobilization in CF patients., Competing Interests: The authors declare no conflict of interest.

Background: For persons with suspected pulmonary tuberculosis, the guidelines of the Centers for Disease Control and Prevention recommend collecting 3 respiratory specimens 8 to 24 hours apart for acid-fast bacilli (AFB) smear and culture, in addition to 1 nucleic acid amplification test (NAAT). However, data supporting this approach are limited. Our objective was to estimate the performance of 1, 2, or 3 AFB smears with or without NAATs to detect pulmonary tuberculosis in a low-prevalence setting., Methods: We conducted a retrospective study of hospitalized persons at 8 Massachusetts acute care facilities who underwent mycobacterial culture on 1 or more respiratory specimens between July 2016 and December 2022. We evaluated percentage positivity and yield on serial AFB smears and NAATs among people with growth of Mycobacterium tuberculosis on mycobacterial cultures., Results: Among 104 participants with culture-confirmed pulmonary tuberculosis, the first AFB smear was positive in 41 cases (39%). A second AFB smear was positive in 11 (22%) of the 49 cases in which it was performed. No third AFB smears were positive following 2 initial negative smears. Of 52 smear-negative cases, 36 had a NAAT performed, leading to 23 additional diagnoses. Overall sensitivity to detect tuberculosis prior to culture positivity was higher in any strategy involving 1 or 2 NAATs (74%-79%), even without AFB smears, as compared with 3 smears alone (60%)., Conclusions: Tuberculosis diagnostic testing with 2 AFB smears offered the same yield as 3 AFB smears while potentially reducing laboratory burden and duration of airborne infection isolation. Use of 1 or 2 NAATs increased sensitivity to detect culture-positive pulmonary tuberculosis when added to AFB smear-based diagnostic testing alone., Competing Interests: Potential conflicts of interest. J. A. B. has received research funding for other studies from Zeus Scientific, Pfizer, and Analog Devices Inc and has been a paid consultant to Roche Diagnostics, Flightpath Biosciences, and Tarsus Pharmaceuticals. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We evaluated the role of Staphylococcus aureus AbcA transporter in bacterial persistence and survival following exposure to the bactericidal agents nafcillin and oxacillin at both the population and single-cell levels. We show that AbcA overexpression resulted in resistance to nafcillin but not oxacillin. Using distinct fluorescent reporters of cell viability and AbcA expression, we found that over 6-14 hours of persistence formation, the proportion of AbcA reporter-expressing cells assessed by confocal microscopy increased sixfold as cell viability reporters decreased. Similarly, single-cell analysis in a high-throughput microfluidic system found a strong correspondence between antibiotic exposure and AbcA reporter expression. Persister cells grown in the absence of antibiotics showed neither an increase in nafcillin MIC nor in abcA transcript levels, indicating that survival was not associated with stable mutational resistance or abcA overexpression. Furthermore, persister cell levels on exposure to 1×MIC and 25×MIC of nafcillin decreased in an abcA knockout mutant. Survivors of nafcillin and oxacillin treatment overexpressed transporter AbcA, contributing to an enrichment of the number of persisters during treatment with pump-substrate nafcillin but not with pump-non-substrate oxacillin, indicating that efflux pump expression can contribute selectively to the survival of a persister population., Competing Interests: The authors declare no conflict of interest.

Endogenous transporters protect Staphylococcus aureus against antibiotics and also contribute to bacterial defense from environmental toxins. We evaluated the effect of overexpression of four efflux pumps, NorA, NorB, NorC, and Tet38, on S. aureus survival following exposure to pyocyanin (PYO) of Pseudomonas aeruginosa , using a well diffusion assay. We measured the PYO-created inhibition zone and found that only an overexpression of NorA reduced S. aureus susceptibility to pyocyanin killing. The MIC PYO of the NorA overexpressor increased threefold compared to that of wild-type RN6390 and was reduced 2.5-fold with reserpine, suggesting that increased NorA efflux caused PYO resistance. The PYO-created inhibition zone of a ΔnorA mutant was consistently larger than that of a plasmid-borne NorA overexpressor. PYO also produced a modest increase in norA expression (1.8-fold at 0.25 µg/mL PYO) that gradually decreased with increasing PYO concentrations. Well diffusion assays carried out using P. aeruginosa showed that ΔnorA mutant was less susceptible to killing by PYO-deficient mutants PA14 phzM and PA14 phzS than to killing by PA14. NorA overexpression led to reduced killing by all tested P. aeruginosa . We evaluated the NorA-PYO interaction using a collection of 22 clinical isolates from adult and pediatric cystic fibrosis (CF) patients, which included both S. aureus (CF-SA) and P. aeruginosa (CF-PA). We found that when isolated alone, CF-PA and CF-SA expressed varying levels of PYO and norA transcripts, but all four CF-PA/CF-SA pairs isolated concurrently from CF patients produced a low level of PYO and low norA transcript levels, respectively, suggesting a partial adaptation of the two bacteria in circumstances of persistent co-colonization., Competing Interests: The authors declare no conflict of interest.

The Selux Next-Generation Phenotyping (NGP) system (Charlestown, MA) is a new antimicrobial susceptibility testing system that utilizes two sequential assays performed on all wells of doubling dilution series to determine MICs. A multicenter evaluation of the performance of the Selux NGP system compared with reference broth microdilution was conducted following FDA recommendations and using FDA-defined breakpoints. A total of 2,488 clinical and challenge isolates were included; gram-negative isolates were tested against 24 antimicrobials, and gram-positive isolates were tested against 15 antimicrobials. Data is provided for all organism-antimicrobial combinations evaluated, including those that did and did not meet FDA performance requirements. Overall very major error and major error rates were less than 1% (31/3,805 and 107/15,606, respectively), essential agreement and categorical agreement were >95%, reproducibility was ≥95%, and the average time-to-result (from time of assay start to time of MIC result) was 5.65 hours., Competing Interests: Authors K.F., B.R.S., K.R.B., S.M., K.R., A.E., M.S., J.C., J.L., K.D., N.S., G.K., F.C., J.D., A.C., A.L., J.S., K.M., A.V., and E.S. are or have been employed by Selux Diagnostics. A.F., J.S.L., M.J.F., S.E.S., M.P.W., and D.C.H. have consulted for Selux Diagnostics.

The chromosomally encoded AmpC beta-lactamase is widely distributed throughout the Enterobacterales. When expressed at high levels through transient induction or stable de-repression, resistance to ceftriaxone, a commonly used antibiotic, can develop. Recent clinical guidance suggests, based on limited evidence, that resistance may be less likely to develop in Serratia marcescens compared to the better-studied Enterobacter cloacae and recommends that ceftriaxone may be used if the clinical isolate tests susceptible. We sought to generate additional data relevant to this recommendation. AmpC de-repression occurs predominantly because of mutation in the ampD peptidoglycan amidohydrolase. We find that, in contrast to E. cloacae , where deletion of ampD results in high-level ceftriaxone resistance (with ceftriaxone MIC = 96 µg/mL), in S. marcescens deletion of two amidohydrolases ( ampD and amiD2 ) is necessary for AmpC de-repression, and the resulting ceftriaxone MIC is 1 µg/mL. Two mechanisms for this difference were identified. We find both a higher relative increase in ampC transcript level in E. cloacae Δ ampD compared to S. marcescens ΔampDΔamiD2 , as well as higher in vivo efficiency of ceftriaxone hydrolysis by the E. cloacae AmpC enzyme compared to the S. marcescens AmpC enzyme. We also observed higher relative levels of transient AmpC induction in E. cloacae vs S. marcescens when exposed to ceftriaxone. In time-kill curves, this difference translates into the survival of E. cloacae but not S. marcescens at clinically relevant ceftriaxone concentrations. In summary, our findings can explain the decreased propensity for on-treatment ceftriaxone resistance development in S. marcescens , thereby supporting recently issued clinical guidance., Competing Interests: The authors declare no conflict of interest.

In the age of antimicrobial resistance, the urgency by which novel therapeutic approaches need to be introduced into the clinical pipeline has reached critical levels. Antimicrobial blue light (aBL), as an alternative approach, has demonstrated promise as a stand-alone therapeutic method, albeit with a limited window of antimicrobial activity. Work by others indicates that treatment with antibiotics increases the production of reactive oxygen species (ROS) which may, in part, contribute to the bactericidal effects of antibiotics. These findings suggest that there may be potential for synergistic interactions with aBL, that similarly generates ROS. Therefore, in this study, the mechanism of aBL is investigated, and the potential for aBL to synergistically promote antibiotic activity is similarly evaluated. Furthermore, the translatability of using aBL and chloramphenicol in combination within a mouse model of Acinetobacter baumanii burn infection is assessed. It is concluded that porphyrins and hydroxyl radicals driven by "free iron" are paramount to the effectiveness of aBL; and aBL is effective at promoting multiple antibiotics in different multidrug-resistant bacteria. Moreover, rROS up-regulation, and promoted antibiotic uptake are observed during aBL+antibiotic exposure. Lastly, aBL combined with chloramphenicol appears to be both effective and safe for the treatment of A. baumannii burn infection. In conclusion, aBL may be a useful adjunct therapy to antibiotics to potentiate their action., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer., Competing Interests: Declaration of Competing Interest FQ is an employee/contractor at Janssen Pharmaceutical. EC is a consultant of Dotquant and received funding under institutional SRA from Janssen Research, Bayer Pharmaceuticals, Forma Therapeutics, Foghorn, Kronos Bios, Genentech, Astra Zeneca, and MacroGenics. No potential conflict of interest was reported by the other authors., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Screening for asymptomatic bacteriuria (ASB) is not recommended outside of patients undergoing invasive urological procedures and during pregnancy. Despite national guidelines recommending against screening for ASB, this practice is prevalent. We present outcomes from a quality-improvement intervention targeting patients undergoing cardiac artery bypass grafting surgery (CABG) at Massachusetts General Hospital, a tertiary-care hospital in Boston, Massachusetts, where preoperative testing checklists were modified to remove routine urinalysis and urine culture. This was a before-and-after intervention study., Methods: Prior to the intervention, screening for ASB was included in the preoperative check list for all patients undergoing CABG. We assessed the proportion of patients undergoing screening for ASB in the 6 months prior to and after the intervention. We estimated cost savings from averted laboratory analyses, and we evaluated changes in antibiotic prescriptions. We additionally examined the incidence of postoperative surgical-site infections (SSIs), central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs) and Clostridioides difficile infections (CDIs)., Results: Comparing the pre- and postintervention periods, urinalyses decreased by 76.5% and urine cultures decreased by 87.0%, with an estimated cost savings of $8,090.38. There were 50% fewer antibiotic prescriptions for bacteriuria after the intervention., Conclusions: Removal of urinalysis and urine culture from preoperative checklists for cardiac surgery led to a statistically significant decrease in testing without an increase in SSIs, CLABSIs, CAUTIs, or CDI. Challenges identified included persistence of checklists in templated order sets in the electronic health record., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Concurrent PD-1 blockade and thoracic radiotherapy is being investigated in clinical trials for locally advanced, non-small cell lung cancer and small cell lung cancer, despite a potential overlapping risk of cardiotoxicity. Our prior studies demonstrate that cardiotoxicity from concurrent cardiac irradiation and anti-PD-1 administration in a mouse model is CD8+ T-cell dependent. The objective of this study was to determine whether humoral immunity contributed to the observed cardiac tissue damage, as measured by creatine kinase MB and cardiac troponin 1 release and decline in cardiac function. In the current study, we demonstrate the presence of cardiac autoantibodies, which were essential for the occurrence of cardiotoxicity from the combined therapy. Mice subjected to cardiac irradiation, while being treated with anti-PD-1, developed high levels of antibodies that reacted with cardiac tissues in vivo and cardiac antigens in vitro. Moreover, mice deficient in B cells were protected against cardiotoxicity, whereas the transfer of autoantibody-containing sera from mice that had received combined treatment reproduced the same pathologic phenotype in mice exposed to cardiac irradiation but was not observed in normal recipients. The cardiotoxic effect of the sera, which associated with CD8+ T-cell accumulation in cardiac tissue, was limited by IgG depletion. In conclusion, concurrent cardiac irradiation and PD-1 blockade leads to production of cardiac autoantibodies, likely due to antigen exposure within the irradiated cardiac tissues, which play a key role in the resulting cardiotoxicity., (©2023 American Association for Cancer Research.)

The coronavirus disease 2019 (COVID-19) pandemic highlighted the lack of agreement regarding the definition of aerosol-generating procedures and potential risk to healthcare personnel. We convened a group of Massachusetts healthcare epidemiologists to develop consensus through expert opinion in an area where broader guidance was lacking at the time., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection is poorly understood, partly because few studies have systematically applied genomic analysis to distinguish reinfection from persistent RNA detection related to initial infection. We aimed to evaluate the characteristics of SARS-CoV-2 reinfection and persistent RNA detection using independent genomic, clinical, and laboratory assessments., Methods: All individuals at a large academic medical center who underwent a SARS-CoV-2 nucleic acid amplification test (NAAT) ≥45 days after an initial positive test, with both tests between 14 March and 30 December 2020, were analyzed for potential reinfection. Inclusion criteria required having ≥2 positive NAATs collected ≥45 days apart with a cycle threshold (Ct) value <35 at repeat testing. For each included subject, likelihood of reinfection was assessed by viral genomic analysis of all available specimens with a Ct value <35, structured Ct trajectory criteria, and case-by-case review by infectious diseases physicians., Results: Among 1569 individuals with repeat SARS-CoV-2 testing ≥45 days after an initial positive NAAT, 65 (4%) met cohort inclusion criteria. Viral genomic analysis characterized mutations present and was successful for 14/65 (22%) subjects. Six subjects had genomically supported reinfection, and 8 subjects had genomically supported persistent RNA detection. Compared to viral genomic analysis, clinical and laboratory assessments correctly distinguished reinfection from persistent RNA detection in 12/14 (86%) subjects but missed 2/6 (33%) genomically supported reinfections., Conclusions: Despite good overall concordance with viral genomic analysis, clinical and Ct value-based assessments failed to identify 33% of genomically supported reinfections. Scaling-up genomic analysis for clinical use would improve detection of SARS-CoV-2 reinfections., Competing Interests: Potential conflicts of interest. M. N. A. is an equity holder and consultant to Day Zero Diagnostics (company does not work on SARS-CoV-2). P. C. S. is a co-founder of, shareholder in, and scientific advisor to Sherlock Biosciences, Inc (2019–present); she is also a Board member of and shareholder in Danaher Corporation (2019–present), and co-founder and consultant to Delve Bio (2022–present). P. C. S. has filed IP related to genome sequencing and analysis. P. C. S. also reports that Sherlock Biosciences has licensed technology from the author and her lab on CRISPR-based diagnostics and has received consulting fees from the same; stock or stock options with Polaris Genomics (investor and future scientific advisory board [SAB] member) and NextGen Jane (former SAB member and investor). I. V. B. reports an unrelated NIH grant number R01AI042006-24S1. E. S. S. reports unrelated grants or contracts from CDC, Assistant Secretary for Preparedness and Response, MIT/Quanta; payment or honoraria as a writer for Up To Date (2022 to current) and for a single lecture on COVID Infection Prevention to Vertex Pharmaceuticals, 2020; roles as President of Massachusetts Infectious Diseases Society, Vice-Chair of Public Policy and Government Affairs Committee, Society for Healthcare Epidemiology of America, and Member of Boston Biosafety Committee, Boston Public Health Commission. K. A. B, reports NIH training grant 5T32 AI007387-32, unrelated to this work. C. M. D. reports grants paid to institution (NIH/National Institute of Child Health and Human Development [NICHD] grant number K08 HD101342; Harvard University Center for AIDS Research [CFAR]; and MGH Executive Committee on Research), payments to institution from CDC; and contracts to institution from International AIDS Vaccine Initiative and NIH/IMPAACT Network. R. C. L. reports grant from CDC: U01-CK000633; UpToDate: Royalties for Authorship; payment or honoraria from CDC Foundation: Editorial Services; a leadership or fiduciary role on the board of Greater Boston Physicians for Social Responsibility. J. E. L. reports consulting fees 2019–2020 from Sherlock Biosciences; and honorarium from Virology Education. E. R. reports participation as PPD member of the Moderna Clinical Endpoint Adjudication Committee. S. E. T. reports royalties from UpToDate; travel support for attending Duke Clinical Research Institute meeting on preparing for the next pandemic; and reports that her husband is a partner and has equity in an economic consulting firm (Analysis Group Inc.) that provides consulting services for life science companies among many others. E. P. H. reports grants or contracts unrelated to this work and paid to institution from NIH and MGH; royalties paid to author from UpToDate. All other authors report no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In May 2022, the first case of monkeypox virus (MPXV) infection in the United States in the current global outbreak was identified. As part of the public health and health care facility response, a contact tracing and exposure investigation was done., Objective: To describe the contact tracing, exposure identification, risk stratification, administration of postexposure prophylaxis (PEP), and exposure period monitoring for contacts of the index patient, including evaluation of persons who developed symptoms possibly consistent with MPXV infection., Design: Contact tracing and exposure investigation., Setting: Multiple health care facilities and community settings in Massachusetts., Participants: Persons identified as contacts of the index patient., Intervention: Contact notification, risk stratification, and symptom monitoring; PEP administration in a subset of contacts., Measurements: Epidemiologic and clinical data collected through standard surveillance procedures at each facility and then aggregated and analyzed., Results: There were 37 community and 129 health care contacts identified, with 4 at high risk, 49 at intermediate risk, and 113 at low or uncertain risk. Fifteen health care contacts developed symptoms during the monitoring period. Three met criteria for MPXV testing, with negative results. Two community contacts developed symptoms. Neither met criteria for MPXV testing, and neither showed disease progression consistent with monkeypox. Among 4 persons with high-risk exposures offered PEP, 3 elected to receive PEP. Among 10 HCP with intermediate-risk exposures for which PEP was offered as part of informed clinical decision making, 2 elected to receive PEP. No transmissions were identified at the conclusion of the 21-day monitoring period, despite the delay in recognition of monkeypox in the index patient., Limitation: Descriptions of exposures are subject to recall bias, which affects risk stratification., Conclusion: In a contact tracing investigation involving 166 community and health care contacts of a patient with monkeypox, no secondary cases were identified., Primary Funding Source: None.

Immune checkpoint inhibitors (ICIs) have led recent advances in the field of cancer immunotherapy improving overall survival in multiple malignancies with abysmal prognoses prior to their introduction. The remarkable efficacy of ICIs is however limited by their potential for systemic and organ specific immune-related adverse events (irAEs), most of which present with mild to moderate symptoms that can resolve spontaneously, with discontinuation of therapy or glucocorticoid therapy. Cardiac irAEs however are potentially fatal. The understanding of autoimmune cardiotoxicity remains limited due to its rareness. In this paper, we provide an updated review of the literature on the pathologic mechanisms, diagnosis, and management of autoimmune cardiotoxicity resulting from ICIs and their combinations and provide perspective on potential strategies and ongoing research developments to prevent and mitigate their occurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Irabor, Nelson, Shah, Niazi, Poiset, Storozynsky, Singla, Hooper and Lu.)

A large, ongoing multicountry outbreak of human monkeypox has the potential to cause considerable morbidity and mortality. Therapeutics for the treatment of smallpox, a related Orthopoxvirus , may be used and affect the natural history of monkeypox. We present 3 patients from our hospitals treated with tecovirimat, a pan- Orthopoxvirus inhibitor currently available under an expanded access investigational new drug protocol for monkeypox., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Staphylococcus aureus Tet38 efflux pump has multiple functions, including conferring resistance to tetracycline and other compounds and enabling internalization and survival within epithelial cells. In this study, we evaluated the effects of sodium and potassium on tet38 expression. These monovalent cations are known to play a role in transport by the related S. aureus TetK and B. subtilis TetL transporters. tet38 transcription decreased with increasing sodium concentrations by means of direct repression by the salt stress-dependent KdpD/E regulator. tet38 transcription increased 20-fold and tetracycline minimum inhibitory concentration (MIC) increased 4-fold in a Δ kdpD mutant. KdpE bound specifically to the tet38 promoter. Under extreme salt stress, the survival of S. aureus with intact tet38 was reduced compared to that of a Δ tet38 mutant. To study the effect of sodium on Tet38 function, we generated constructs overexpressing tet38 and tetK and introduced them into Escherichia coli TO114, which is deficient in major sodium transporters. Tet38 tetracycline efflux was directly demonstrated in a fluorescence assay, and tetracycline efflux of both Tet38 and TetK was abolished by the protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In contrast, NaCl inhibited efflux by Tet38 but not TetK, whereas KCl inhibited efflux by TetK but not Tet38. Cell-associated Na increased with heterologous overexpression of Tet38. These data indicate that S. aureus Tet38 is a tetracycline efflux pump regulated by the KdpD/E regulator. Under salt stress, S. aureus adjusted its survival in part by reducing the expression of tet38 through KdpD/E. The mechanisms by which Tet38 is detrimental to salt tolerance in S. aureus and inhibited by sodium remain to be determined. IMPORTANCE This study shows that S. aureus Tet38 is a tetracycline efflux pump regulated by KdpD/E regulator. These findings are the first direct demonstration of Tet38-mediated tetracycline efflux, which had previously been inferred from its ability to confer tetracycline resistance. Under salt stress, S. aureus adjusts its survival in part by reducing the expression of tet38 through KdpD/E. We demonstrated the differences in the respective functions of S. aureus Tet38 and other tetracycline efflux transporters (S. aureus TetK, B. subtilis TetL) regarding their transport of tetracycline and Na + /K + . Notably, sodium selectively reduced tetracycline efflux by Tet38, and potassium selectively reduced tetracycline efflux by TetK. The multiple functions of Tet38 emphasize its importance in bacterial adaptation to and survival in diverse environments.

The authors describe infection prevention and control approaches to severe acute respiratory syndrome coronavirus 2 in the health care setting, including a review of the chain of transmission and the hierarchy of controls, which are cornerstones of infection control and prevention. The authors also discuss lessons learned from nosocomial transmission events., Competing Interests: Disclosure None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms., Methods: To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years., Results: Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment., Conclusions: Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks., (© 2022. The Author(s).)

Mupirocin induced expression of genes encoding efflux pumps NorA and MepA as well as a yellow fluorescent protein (YFP) fluorescence reporter of NorA. Mupirocin exposure also produced reduced susceptibility to pump substrates ciprofloxacin and chlorhexidine, a change that was dependent on intact norA and mepA , respectively.

Background: Isolation of hospitalized persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19) reduces nosocomial transmission risk. Efficient evaluation of PUIs is needed to preserve scarce healthcare resources. We describe the development, implementation, and outcomes of an inpatient diagnostic algorithm and clinical decision support system (CDSS) to evaluate PUIs., Methods: We conducted a pre-post study of CORAL (COvid Risk cALculator), a CDSS that guides frontline clinicians through a risk-stratified COVID-19 diagnostic workup, removes transmission-based precautions when workup is complete and negative, and triages complex cases to infectious diseases (ID) physician review. Before CORAL, ID physicians reviewed all PUI records to guide workup and precautions. After CORAL, frontline clinicians evaluated PUIs directly using CORAL. We compared pre- and post-CORAL frequency of repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs), time from NAAT result to PUI status discontinuation, total duration of PUI status, and ID physician work hours, using linear and logistic regression, adjusted for COVID-19 incidence., Results: Fewer PUIs underwent repeated testing after an initial negative NAAT after CORAL than before CORAL (54% vs 67%, respectively; adjusted odd ratio, 0.53 [95% confidence interval, .44-.63]; P < .01). CORAL significantly reduced average time to PUI status discontinuation (adjusted difference [standard error], -7.4 [0.8] hours per patient), total duration of PUI status (-19.5 [1.9] hours per patient), and average ID physician work-hours (-57.4 [2.0] hours per day) (all P < .01). No patients had a positive NAAT result within 7 days after discontinuation of precautions via CORAL., Conclusions: CORAL is an efficient and effective CDSS to guide frontline clinicians through the diagnostic evaluation of PUIs and safe discontinuation of precautions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Serratia marcescens, a member of the order Enterobacterales, is adept at colonizing health care environments and is an important cause of invasive infections. Antibiotic resistance is a daunting problem in S. marcescens because, in addition to plasmid-mediated mechanisms, most isolates have considerable intrinsic resistance to multiple antibiotic classes. To discover endogenous modifiers of antibiotic susceptibility in S. marcescens, a high-density transposon insertion library was subjected to sub-MICs of two cephalosporins, cefoxitin, and cefepime, as well as the fluoroquinolone ciprofloxacin. Comparisons of transposon insertion abundance before and after antibiotic exposure identified hundreds of potential modifiers of susceptibility to these agents. Using single-gene deletions, we validated several candidate modifiers of cefoxitin susceptibility and chose ydgH , a gene of unknown function, for further characterization. In addition to cefoxitin, deletion of y dgH in S. marcescens resulted in decreased susceptibility to multiple third-generation cephalosporins and, in contrast, to increased susceptibility to both cationic and anionic detergents. YdgH is highly conserved throughout the Enterobacterales, and we observed similar phenotypes in Escherichia coli O157:H7 and Enterobacter cloacae mutants. YdgH is predicted to localize to the periplasm, and we speculate that it may be involved there in cell envelope homeostasis. Collectively, our findings provide insight into chromosomal mediators of antibiotic resistance in S. marcescens and will serve as a resource for further investigations of this important pathogen.

Background: Cutaneous mold infections commonly result from an array of traumatic injuries that involve direct inoculation of contaminated soil into wounds. Here, we explored the use of antimicrobial blue light (aBL; 405 nm wavelength) and the combination of aBL with quinine hydrochloride (aBL + Q-HCL) for the treatment of cutaneous mold infections., Methods: Efficacy of aBL and aBL + Q-HCL in killing clinically important pathogenic molds (Aspergillus fumigatus, Aspergillus flavus, and Fusarium oxyprorum) was investigated. Ultraperformance liquid chromatography identified and quantified endogenous porphyrins in the mold conidia. Finally, a mouse model of dermabrasion wound infected with a bioluminescent variant of A. fumigatus was developed to investigate the efficacy of aBL in treating cutaneous mold infections., Results: We demonstrated that mold conidia are tolerant to aBL, but Q-HCL enhances efficacy. Transmission electron microscopy revealed intracellular damage by aBL. aBL + Q-HCL resulted in intracellular and cell wall damage. Porphyrins were observed in all mold strains, with A. fumigatus having the highest concentration. aBL and aBL + Q-HCL effectively reduced the burden of A. fumigatus within an established dermabrasion infection and limited recurrence posttreatment., Conclusions: aBL and aBL + Q-HCL may offer a novel approach for the treatment of mold infections., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The difficulty in treatment of glioblastoma is a consequence of its natural infiltrative growth and the existence of a population of therapy-resistant glioma cells that contribute to growth and recurrence. To identify cells more likely to have these properties, we examined the expression in tumor specimens of several protein markers important for glioma progression including the intermediate filament protein, Nestin (NES), a glucose transporter (Glut1/SLC2A1), the glial lineage marker, glial fibrillary acidic protein, and the proliferative indicator, Ki-67. We also examined the expression of von Willebrand factor, a marker for endothelial cells as well as the macrophage/myeloid markers CD163 and CD15. Using a multicolor immunofluorescence and hematoxylin and eosin staining approach with archival formalin-fixed, paraffin embedded tissue from primary, recurrent, and autopsy IDH1 wildtype specimens combined with high-resolution tissue image analysis, we have identified highly proliferative NES(+)/Glut1(-) cells that are preferentially perivascular. In contrast, Glut1(+)/NES(-) cells are distant from blood vessels, show low proliferation, and are preferentially located at the borders of pseudopalisading necrosis. We hypothesize that Glut1(+)/NES(-) cells would be naturally resistant to conventional chemotherapy and radiation due to their low proliferative capacity and may act as a reservoir for tumor recurrence., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

The Qnr pentapeptide repeat proteins interact with DNA gyrase and protect it from quinolone inhibition. The two external loops, particularly the larger loop B, of Qnr proteins are essential for quinolone protection of DNA gyrase. The specific QnrB1 interaction sites on DNA gyrase are not known. In this study, we investigated the interaction between GyrA and QnrB1 using site-specific photo-cross-linking of QnrB1 loop B combined with mass spectrometry. We found that amino acid residues 286 to 298 on the tower domain of GyrA interact with QnrB1 and play a key role in QnrB1 protection of gyrase from quinolone inhibition. Alanine replacement of arginine at residue 293 and a small deletion of amino acids 286 to 289 of GyrA resulted in a decrease in the QnrB1-mediated increase in quinolone MICs and also abolished the QnrB1 protection of purified DNA gyrase from ciprofloxacin inhibition.

Among hospitalized persons under investigation for coronavirus disease 2019 (COVID-19), more repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs) after a negative NAAT were positive from lower than from upper respiratory tract specimens (1.9% vs 1.0%, P = .033). Lower respiratory testing should be prioritized among patients displaying respiratory symptoms with moderate-to-high suspicion for COVID-19 after 1 negative upper respiratory NAAT., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The worldwide distribution of qnr genes found on plasmids and their presence on the chromosomes of aquatic bacteria, such as Vibrio vulnificus , one of the suspected sources, suggests an origin before the development of synthetic quinolones. However, their native function remains unknown. Previous work indicated that expression of qnrVv in V. vulnificus was induced by cold shock. To investigate its role further, we constructed single in-frame deletion mutants in qnrVv and cspA (the gene for cold shock protein) and a double mutant in qnrVv and cspA in V. vulnificus ATCC 17562 to evaluate the response to different environmental conditions and stresses and to exposure to various DNA-damaging agents. We found that qnrVv is involved in resistance to ciprofloxacin, levofloxacin, and mitomycin C and in the cold shock response in V. vulnificus Moreover, Δ qnrVv and Δ cspA mutants showed slower growth when they were treated with bile salts at 37°C and then shifted to 15°C (cold shock) without bile salts in the medium, with the effect being stronger in the double mutant. This transition may mimic what happens when V. vulnificus is ingested into the gastrointestinal tract and released in its natural environment. Cold shock and bile salts induced the expression of cspA and DNA gyrase and topoisomerase IV genes. However, no induction was found in the Δ qnrVv mutant, suggesting that the qnrVv gene is involved in the response to DNA damage and nucleic acid secondary structure., (Copyright © 2021 American Society for Microbiology.)

The Staphylococcus aureus Tet38 membrane protein has distinct functions, including drug efflux and host cell attachment and internalization mediated by interaction with host cell CD36. Using structural modeling and site-directed mutagenesis, we identified key amino acids involved in different functions. Tet38, a member of the major facilitator superfamily, is predicted to have 14 transmembrane segments (TMS), 6 cytoplasmic loops, and 7 external loops. Cysteine substitutions of arginine 106 situated at the junction of TMS 4 and external loop L2, and glycine 151 of motif C on TMS 5, resulted in complete or near-complete (8- to 16-fold) reductions in Tet38-mediated resistance to tetracycline, with minimal to no effect on A549 host cell internalization. In contrast, a three-amino-acid deletion, F 411 P 412 G 413 , in external loop L7 situated between TMS 13 and 14 led to a decrease of 4-fold in S. aureus internalization by A549 cells and a partial effect on tetracycline resistance (4-fold reduction). A three-amino-acid deletion, D 38 D 39 L 40 , in external loop L1 situated between TMS-1 and TMS-2, had a similar partial effect on tetracycline resistance but did not affect cell internalization. Using an Ni column retention assay, we showed further that the L7, but not the L1, deletion impaired binding to CD36. Thus, the L7 domain of Tet38 is key for interaction with CD36 and host cell internalization, and amino acids R 106 and G 151 (TMSs 4 and 5) are particularly important for tetracycline resistance without affecting internalization., (Copyright © 2021 American Society for Microbiology.)

Patients with grade III anaplastic astrocytomas (AA) separate into survival cohorts based on the presence or absence of mutations in isocitrate dehydrogenase (IDH). Progression to glioblastoma (GBM), morphologically distinguishable by elevated microvascular proliferation, necrosis, and cell division in tumor tissues, is considerably more rapid in IDH wild-type tumors such that their diagnosis as AA is relatively rare. More often initially presenting as GBM, these contain higher numbers of tumor-associated macrophages (TAMs) than most AA, and GBM patients also have higher levels of circulating M2 monocytes. TAM and M2 monocytes share functional properties inhibitory for antitumor immunity. Yet, although there is a wealth of data implicating TAM in tumor-immune evasion, there has been limited analysis of the impact of the circulating M2 monocytes. In the current study, immune parameters in sera, circulating cells, and tumor tissues from patients with primary gliomas morphologically diagnosed as AA were assessed. Profound differences in serum cytokines, glioma extracellular vesicle cross-reactive Abs, and gene expression by circulating cells identified two distinct patient cohorts. Evidence of type 2-immune bias was most often seen in patients with IDH wild-type AA, whereas a type 1 bias was common in patients with tumors expressing the IDH1R132H mutation. Nevertheless, a patient's immune profile was better correlated with the extent of tumor vascular enhancement on magnetic resonance imaging than IDH mutational status. Regardless of IDH genotype, AA progression appears to be associated with a switch in systemic immune bias from type 1 to type 2 and the loss of tumor vasculature integrity., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma., Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies., Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall ( n = 22; P = 0.001) and 17.1 months at the highest exposure ( n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O 6 -methylguanine-DNA methyltransferase promoter ( n = 10) demonstrated median PFS of 38.4 months ( P = 0.0008). Evidence of immune activation was noted., Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583)., (©2021 American Association for Cancer Research.)

We describe an approach to the evaluation and isolation of hospitalized persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19) at a large US academic medical center. Only a small proportion (2.9%) of PUIs with 1 or more repeated severe acute respiratory coronavirus virus 2 (SARS-CoV-2) nucleic acid amplification tests (NAATs) after a negative NAAT were diagnosed with COVID-19.