Activation of Alveolar Epithelial ER Stress by ß-Coronavirus Infection Disrupt Surfactant Homeostasis in Mice: Implications for Covid-19 Respiratory Failure.

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar Type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, SARS-CoV-2 and other ß-coronavirus genus members induce an ER stress response in vitro, however the consequences for host AT2 function in vivo are less understood. To study this, two murine models of coronavirus infection were employed- mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse adapted SARS-CoV-2 strain. MHV-1 infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased IRE1α signaling and a biphasic response in PERK signaling accompanied marked reductions in AT2 and BALF surfactant protein (SP-B, SP-C) content, increases in surfactant surface tension, and emergence of a re-programmed epithelial cell population (Krt8+, Cldn4+). The loss of a homeostatic AT2 endophenotype was attenuated by treatment with the IRE1α inhibitor OPK711. As proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from ß-coronavirus infection results from an aberrant host response activating multiple AT2 UPR pathways, altering surfactant metabolism/function, and changing AT2 endophenotypes offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure.

Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10-9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10-16 and CPA3; p = 2.39 × 10-14) and wound healing (FN1; p = 7.63 × 10-9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora.

Association between infectious diseases consultation and mortality in hospitalized patients with Gram-negative bloodstream infection: a retrospective population-wide cohort study.

OBJECTIVES: Data supporting routine infectious diseases (ID) consultation in Gram-negative bloodstream infection (GN-BSI) are limited. We evaluated the association between ID consultation and mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario using linked health administrative databases. METHODS: Hospitalized adult patients with GN-BSI between April 2017 and December 2021 were included. The primary outcome was time to all-cause mortality censored at 30 days, analyzed using a mixed effects Cox proportional hazards model with hospital as a random effect. ID consultation 1-10 days after the first positive blood culture was treated as a time-varying exposure. RESULTS: Of 30,159 patients with GN-BSI across 53 hospitals, 11,013 (36.5%) received ID consultation. Median prevalence of ID consultation for patients with GN-BSI across hospitals was 35.0% with wide variability (range 2.7-76.1%, interquartile range 19.6-41.1%). 1041 (9.5%) patients who received ID consultation died within 30 days, compared to 1797 (9.4%) patients without ID consultation. In the fully-adjusted multivariable model, ID consultation was associated with mortality benefit (adjusted HR 0.82, 95% CI 0.77-0.88, p < 0.0001; translating to absolute risk reduction of -3.8% or NNT of 27). Exploratory subgroup analyses of the primary outcome showed that ID consultation could have greater benefit in patients with high-risk features (nosocomial infection, polymicrobial or non-Enterobacterales infection, antimicrobial resistance, or non-urinary tract source). CONCLUSIONS: Early ID consultation was associated with reduced mortality in patients with GN-BSI. If resources permit, routine ID consultation for this patient population should be considered to improve patient outcomes.

Pars plana vitrectomy and scleral-fixated intraocular lenses: comparison of Gore-Tex suture and flanged intrascleral haptic fixation techniques.

OBJECTIVE: To compare clinical outcomes of combined pars plana vitrectomy (PPV) and secondary scleral fixation of an intraocular lens (IOL) using Gore-Tex suture versus flanged intrascleral haptic fixation (FIHF) using double needles. DESIGN: Single-centre retrospective cohort series. PARTICIPANTS: Eyes undergoing PPV with simultaneous scleral fixation of an IOL. METHOD: Eyes that underwent fixation of a Bausch & Lomb Akreos AO60 or enVista MX60E IOL using Gore-Tex suture or a Tecnis ZA9003 or Zeiss CT LUCIA 602 IOL using FIHF were included. The primary outcome was change from baseline visual acuity to postoperative month 3. Secondary outcomes included deviation from refractive target aim and rates of postoperative complications. RESULTS: Seventy-nine eyes of 72 patients were included. Mean (±SD) follow-up was 16 ± 10.5 months (range, 4.5-45.2 months). Fifty-three eyes (67.1%) underwent Gore-Tex suture fixation, and 26 eyes (32.9%) underwent FIHF. Across all eyes, mean visual acuity improved from 1.30 ± 0.74 logMAR (20/399 Snellen equivalent) preoperatively to 0.36 ± 0.36 logMAR (20/45 Snellen equivalent) at 3 months (p < 0.001). No difference in visual acuity at month 3 was noted between the 2 techniques (p = 0.34). Mean deviation from refractive target aim was not significantly different between the Gore-Tex and FIHF groups (+0.14 ± 1.33 D vs -0.16 ± 0.88 D; p = 0.45). Reoperation rates were similar between groups (2 of 53 eyes in the Gore-Tex group vs 3 of 26 eyes in the FIHF group; p = 0.32). CONCLUSION: Combined PPV and scleral fixation of IOLs with Gore-Tex suture and FIHF resulted in similar improvements in visual acuity. No significant differences in refractive outcome and postoperative complication profiles were noted.

Magnetic Resonance Elastography and Computational Modeling Identify Heterogeneous Lung Biomechanical Properties during Cystic Fibrosis.

The lung is a dynamic mechanical organ and several pulmonary disorders are characterized by heterogeneous changes in the lung's local mechanical properties (i.e. stiffness). These alterations lead to abnormal lung tissue deformation (i.e. strain) which have been shown to promote disease progression. Although heterogenous mechanical properties may be important biomarkers of disease, there is currently no non-invasive way to measure these properties for clinical diagnostic purposes. In this study, we use a magnetic resonance elastography technique to measure heterogenous distributions of the lung's shear stiffness in healthy adults and in people with Cystic Fibrosis. Additionally, computational finite element models which directly incorporate the measured heterogenous mechanical properties were developed to assess the effects on lung tissue deformation. Results indicate that consolidated lung regions in people with Cystic Fibrosis exhibited increased shear stiffness and reduced spatial heterogeneity compared to surrounding non-consolidated regions. Accounting for heterogenous lung stiffness in healthy adults did not change the globally averaged strain magnitude obtained in computational models. However, computational models that used heterogenous stiffness measurements predicted significantly more variability in local strain and higher spatial strain gradients. Finally, computational models predicted lower strain variability and spatial strain gradients in consolidated lung regions compared to non-consolidated regions. These results indicate that spatial variability in shear stiffness alters local strain and strain gradient magnitudes in people with Cystic Fibrosis. This imaged-based modeling technique therefore represents a clinically viable way to non-invasively assess lung mechanics during both health and disease.

Facile sonochemically-assisted bioengineering of titanium dioxide nanoparticles and deciphering their potential in treating breast and lung cancers: biological, molecular, and computational-based investigations.

Combining sonochemistry with phytochemistry is a modern trend in the biosynthesis of metallic nanoparticles (NPs), which contributes to the sustainability of chemical processes and minimizes hazardous effects. Herein, titanium dioxide (TiO2) NPs were bioengineered using a novel and facile ultrasound-assisted approach utilizing the greenly extracted essential oil of Ocimum basilicum. FTIR and UV-Vis spectrophotometry were used to confirm the formation of TiO2 NPs. The X-ray diffraction (XRD) analysis showed the crystalline nature of TiO2 NPs. TEM analysis revealed the spherical morphology of the NPs with sizes ranging from 5.55 to 13.89 nm. Energy-dispersive X-ray (EDX) confirmed the purity of the greenly synthesized NPs. TiO2 NPs demonstrated outstanding antitumor activity against breast (MCF-7) and lung (A-549) cancer cells with estimated IC50 values of 1.73 and 4.79 µg mL-1. The TiO2 NPs were cytocompatible to normal cells (MCF-10A) with a selectivity index (SI) of 8.77 for breast and 3.17 for lung cancer. Biological assays revealed a promising potential for TiO2 NPs to induce apoptosis and arrest cells at the sub-G1 phase of the cell cycle phase in both cancer cell lines. Molecular investigations showed the ability of TiO2 NPs to increase apoptotic genes' expression (Bak and Bax) and their profound ability to elevate the expression of apoptotic proteins (caspases 3 and 7). Molecular docking demonstrated strong binding interactions for TiO2 NPs with caspase 3 and EGFR-TK targets. In conclusion, the greenly synthesized TiO2 NPs exhibited potent antitumor activity and mitochondrion-based cell death against breast and lung cancer cell lines while maintaining cytocompatibility against normal cells.

A Micro-scale Humanized Ventilator-on-a-Chip to Examine the Injurious Effects of Mechanical Ventilation.

Patients with compromised respiratory function frequently require mechanical ventilation to survive. Unfortunately, non-uniform ventilation of injured lungs generates complex mechanical forces that lead to ventilator induced lung injury (VILI). Although investigators have developed lung-on-a-chip systems to simulate normal respiration, modeling the complex mechanics of VILI as well as the subsequent recovery phase is a challenge. Here we present a novel humanized in vitro ventilator-on-a-chip (VOC) model of the lung microenvironment that simulates the different types of injurious forces generated in the lung during mechanical ventilation. We used transepithelial/endothelial electrical resistance (TEER) measurements to investigate how individual and simultaneous application of the different mechanical forces alters real-time changes in barrier integrity during and after injury. We find that compressive stress (i.e. barotrauma) does not significantly alter barrier integrity while over-distention (20% cyclic radial strain, volutrauma) results in decreased barrier integrity that quickly recovers upon removal of mechanical stress. Conversely, surface tension forces generated during airway reopening (atelectrauma), result in a rapid loss of barrier integrity with a delayed recovery relative to volutrauma. Simultaneous application of cyclic stretching (volutrauma) and airway reopening (atelectrauma), indicate that the surface tension forces associated with reopening fluid-occluded lung regions is the primary driver of barrier disruption. Thus, our novel VOC system can monitor the effects of different types of injurious forces on barrier disruption and recovery in real-time and can be used to identify the biomechanical mechanisms of VILI.

An Analysis of Solicitations From Predatory Journals in Ophthalmology.

PURPOSE: To evaluate trends associated with email communication from potentially predatory publishers to faculty in ophthalmology. DESIGN: Cross-sectional study METHODS: Ophthalmologists (n = 14) from various subspecialties and institutions were recruited to participate. Participants identified unsolicited emails that they had received originating from publishers in May 2021. Information collected included details on email contents and publisher organizations. Trends in communications from predatory publishers were evaluated. RESULTS: Over a 30-day study period, a total of 1813 emails were received from 383 unique publishers and 696 unique journals, with a mean (SD) of 4.73 (2.46) emails received per day per participant. Of the 1813 emails identified, 242 (13%) emails were invitations to conferences, whereas 1440 (80%) were solicitations for article submissions to open-access, pay-to-publish journals. A total of 522 (29.0%) emails were related to ophthalmology, and reference to a prior publication of the participant occurred in 262 emails (14%). Of the 696 unique journals identified, 174 (25%) journals were indexed on PubMed and 426 (61%) were listed on Beall's list. When comparing journals that were listed on PubMed vs those that were not, PubMed indexed journals had a higher impact factor (2.1 vs 1.5, P = .002), were less likely to use "greetings" (76% vs 91%, P < .001), had fewer spelling/grammar errors (40% vs 51%, P = .01), and were less likely to offer rapid publication (16% vs 25%, P = .02). CONCLUSIONS: Unsolicited requests to publish occur frequently and may diminish the quality of the scientific literature. We encourage individuals in ophthalmology to be aware of these trends in predatory publishing.

Follow-up blood cultures do not reduce mortality in hospitalized patients with Gram-negative bloodstream infection: a retrospective population-wide cohort study.

OBJECTIVES: The utility of follow-up blood cultures (FUBCs) in patients with Gram-negative bloodstream infection (GN-BSI) is controversial. Observational studies have suggested significant mortality benefit but may be limited by single-centre designs, immortal time bias, and residual confounding. We examined the impact of FUBCs on mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario, Canada. METHODS: Adult patients with GN-BSI hospitalized between April 2017 and December 2021 were included. Primary outcome was all-cause mortality within 30 days. FUBC was treated as a time-varying exposure. Secondary outcomes were 90-day mortality, length of stay, and number of days alive and out of hospital at 30 and 90 days. RESULTS: Thirty-four thousand one hundred patients were included; 8807 (25.8%) patients received FUBC, of which 966 (11.0%) were positive. Median proportion of patients receiving FUBC was 18.8% (interquartile range, 10.0-29.7%; range, 0-66.1%) across 101 hospitals; this correlated with positivity and contamination rate. Eight hundred ninety (10.1%) patients in the FUBC group and 2263 (8.9%) patients in the no FUBC group died within 30 days. In the fully adjusted model, there was no association between FUBC and mortality (hazard ratio, 0.97; 95% CI, 0.90-1.04). Patients with FUBC had significantly longer length of stay (median, 11 vs. 7 days; adjusted risk ratio, 1.18; 95% CI, 1.16-1.21) and fewer number of days alive and out of hospital at 30 and 90 days. DISCUSSION: FUBC collection in patients with GN-BSI varies widely across hospitals and may be associated with prolonged hospitalization without clear survival benefit. Residual confounding may be present given the observational design. Clear benefit should be demonstrated in a randomized trial before widespread adoption of routine FUBC.

Risk of Endophthalmitis Based on Cumulative Number of Anti-VEGF Intravitreal Injections.

PURPOSE: To determine the risk of endophthalmitis in eyes undergoing intravitreal injections (IVIs) of anti-VEGF based on cumulative number of injections per eye. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients from a single center undergoing IVIs of ranibizumab, aflibercept, or bevacizumab. METHODS: Eyes were divided into quartiles based on injection number causative of endophthalmitis between January 1, 2011, and June 1, 2022. MAIN OUTCOME MEASURES: Interquartile clinical outcomes and cumulative risk of endophthalmitis per injection and per eye. RESULTS: A total of 43 393 eyes received 652 421 anti-VEGF injections resulting in 231 endophthalmitis cases (0.035% per injection, 1 in 2857), of which 215 were included. The cumulative endophthalmitis risk increased from 0.0018% (1 in 55 556) after 1 injection to 0.013% (1 in 7692) after 11 injections (0.0012 percentage point change), versus 0.014% (1 in 7143) after 12 injections to 0.025% (1 in 4000) after 35 injections (0.00049 percentage point change), versus 0.025% (1 in 4000) after 36 injections to 0.031% (1 in 3226) after 66 injections (0.00017 percentage point change), versus 0.031% (1 in 3226) after 63 injections to 0.033% (1 in 3030) after 126 injections (0.000042 percentage point change) (P < 0.001). Likewise, the cumulative endophthalmitis risk per eye increased from 0.028% (1 in 3571) to 0.20% (1 in 500) between injections 1 and 11 (0.018 percentage point change), versus 0.21% (1 in 476) to 0.38% (1 in 263) between injections 12 and 35 (0.0075 percentage point change), versus 0.38% (1 in 263) to 0.46% (1 in 217) between injections 36 and 66 (0.0026 percentage point change), versus 0.46% (1 in 217) to 0.50% (1 in 200) between injections 67 and 126 (0.00063 percentage point change) (P < 0.001). CONCLUSIONS: The cumulative endophthalmitis risk per injection and per eye increased with greater number of injections received but appeared to do so at a higher rate during earlier injections and at a lower rate further into the treatment course. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Innovative microwave-assisted biosynthesis of copper oxide nanoparticles loaded with platinum(ii) based complex for halting colon cancer: cellular, molecular, and computational investigations.

In the current study, we biosynthesized copper oxide NPs (CuO NPs) utilizing the essential oils extracted from Boswellia carterii oleogum resin, which served as a bioreductant and capping agent with the help of microwave energy. Afterwards, the platinum(ii) based anticancer drug, carboplatin (Cr), was loaded onto the CuO NPs, exploiting the electrostatic interactions forming Cr@CuO NPs. The produced biogenic NPs were then characterized using zeta potential (ZP), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction spectroscopy (XRD), and Fourier transform infrared spectroscopy (FTIR) techniques. In addition, the entrapment efficiency and release profile of the loaded Cr were evaluated. Thereafter, SRB assay was performed, where Cr@CuO NPs demonstrated the highest cytotoxic activity against human colon cancer cells (HCT-116) with an IC50 of 5.17 µg mL-1, which was about 1.6 and 2.2 folds more than that of Cr and CuO NPs. Moreover, the greenly synthesized nanoparticles (Cr@CuO NPs) displayed a satisfactory selectivity index (SI = 6.82), which was far better than the free Cr treatment (SI = 2.23). Regarding the apoptosis assay, the advent of Cr@CuO NPs resulted in an immense increase in the cellular population percentage of HCT-116 cells undergoing both early (16.02%) and late apoptosis (35.66%), significantly surpassing free Cr and CuO NPs. A study of HCT-116 cell cycle kinetics revealed the powerful ability of Cr@CuO NPs to trap cells in the Sub-G1 and G2 phases and impede the G2/M transition. RT-qPCR was utilized for molecular investigations of the pro-apoptotic (Bax and p53) and antiapoptotic genes (Bcl-2). The novel Cr@CuO NPs treatment rose above single Cr or CuO NPs therapy in stimulating the p53-Bax mediated mitochondrial apoptosis. The cellular and molecular biology investigations presented substantial proof of the potentiated anticancer activity of Cr@CuO NPs and the extra benefits that could be obtained from their use.

State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

Risk factors for surgical failure after primary scleral buckling for rhegmatogenous retinal detachment.

OBJECTIVE: To identify risk factors for surgical failure after scleral buckling (SB) for primary rhegmatogenous retinal detachment (RRD) repair. DESIGN: Single-centre retrospective consecutive case series. PARTICIPANTS: All patients who underwent SB for repair of primary RRD at Wills Eye Hospital between January 1, 2015, and December 31, 2018, were included. METHODS: Single-surgery anatomic success (SSAS) rate and risk factors associated with surgical failure were evaluated. A multivariable logistic regression model was completed to assess the effect of demographic, clinical, and operative variables on SSAS rate. RESULTS: A total of 499 eyes of 499 patients were included. Overall SSAS rate was 86% (n = 430 of 499). Using multivariate analysis, surgical failure was more likely in males (adjusted odds ratio [adjusted OR] = 2.98; 95% CI, 1.58-5.62; p = 0.0007) with a macula-off status on preoperative examination (adjusted OR = 2.15; 95% CI, 1.10-4.20; p = 0.03) and preoperative proliferative vitreoretinopathy (adjusted OR = 4.26; 95% CI, 1.10-16.5; p = 0.04). Time interval between initial examination and surgery (p = 0.26), distribution of buckle or band material used (p = 0.88), and distribution of tamponade used (p = 0.74) were not significantly different between eyes with and without surgical failure. CONCLUSION: Male sex, macula-off status, and preoperative proliferative vitreoretinopathy were factors with increased odds of surgical failure after SB for primary RRD repair. Operative characteristics, such as type of band or use of tamponade, were not associated with surgical failure.

First Canadian report of transmission of fluconazole-resistant Candida parapsilosis within two hospital networks confirmed by genomic analysis.

Candida parapsilosis is a common cause of non-albicans candidemia. It can be transmitted in healthcare settings resulting in serious healthcare-associated infections and can develop drug resistance to commonly used antifungal agents. Following a significant increase in the percentage of fluconazole (FLU)-nonsusceptible isolates from sterile site specimens of patients in two Ontario acute care hospital networks, we used whole genome sequence (WGS) analysis to retrospectively investigate the genetic relatedness of isolates and to assess potential in-hospital spread. Phylogenomic analysis was conducted on all 19 FLU-resistant and seven susceptible-dose dependent (SDD) isolates from the two hospital networks, as well as 13 FLU susceptible C. parapsilosis isolates from the same facilities and 20 isolates from patients not related to the investigation. Twenty-five of 26 FLU-nonsusceptible isolates (resistant or SDD) and two susceptible isolates from the two hospital networks formed a phylogenomic cluster that was highly similar genetically and distinct from other isolates. The results suggest the presence of a persistent strain of FLU-nonsusceptible C. parapsilosis causing infections over a 5.5-year period. Results from WGS were largely comparable to microsatellite typing. Twenty-seven of 28 cluster isolates had a K143R substitution in lanosterol 14-α-demethylase (ERG11) associated with azole resistance. As the first report of a healthcare-associated outbreak of FLU-nonsusceptible C. parapsilosis in Canada, this study underscores the importance of monitoring local antimicrobial resistance trends and demonstrates the value of WGS analysis to detect and characterize clusters and outbreaks. Timely access to genomic epidemiological information can inform targeted infection control measures.

Early diagnosis of monomicrobial Clostridioides difficile bacteremia in a patient without colitis.

Bacteremia is a rare finding among Clostridioides difficile infections. We describe a case of a 67-year-old man with resected colorectal cancer with colostomy who presented with small bowel obstruction and was admitted for lysis of adhesions. On day 8 of admission, he developed leukocytosis and raised inflammatory markers with isolation of Gram-positive bacilli in several blood cultures, which was presumptively identified through blood culture pelleting and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) as C. difficile. The diagnosis was confirmed with conventional culture and reference lab identification and the patient demonstrated clinical response with parenteral then oral vancomycin that briefly worsened when therapy was switched to parenteral metronidazole and then improved once oral vancomycin was resumed. Our case was notable in that the combination of pelleting and MALDI-TOF offered early diagnosis in this patient whose positive blood cultures were suspicious for contamination and in whom there was an absence of diarrheal illness or features of colitis on abdominal imaging. Early diagnosis is critical for the timely initiation of therapy, implementation of infection prevention and control measures and in selection of appropriate therapy for antimicrobial stewardship.

La bactériémie est rare lors d'une infection à Clostridioides difficile. Les auteurs décrivent le cas d'un homme de 67 ans ayant une colostomie découlant de la résection d'un cancer colorectal, qui a consulté à cause d'une occlusion du grêle et a été hospitalisé pour traiter des adhésiolyses. Le huitième jour de l'hospitalisation, il a présenté une leucocytose et une augmentation des marqueurs inflammatoires, des bacilles à Gram positif ont été isolés dans plusieurs hémocultures, et un diagnostic provisoire de C. difficile a été posé par culot de sang et désorption/ionisation laser assistée par matrice par temps de vol (MALDI-TOF). Le diagnostic a été confirmé par une culture classique et par le laboratoire de référence, et le patient a affiché une réponse clinique à la vancomycine par voie parentérale, puis par voie orale. Son état s'est brièvement aggravé lors du passage au métronidazole par voie parentérale, puis s'est amélioré à la reprise de la vancomycine par voie orale. Le cas était remarquable parce que la combinaison du culot et de la MALDI-TOF a permis d'obtenir un diagnostic rapide chez ce patient dont les hémocultures positives ont suggéré une contamination dont l'imagerie abdominale ne révélait pas de maladie diarrhéique ni de caractéristiques de colite. Il est essentiel de poser un diagnostic précoce pour entreprendre le traitement rapidement, adopter des mesures de prévention et de contrôle des infections et sélectionner le traitement approprié à la gouvernance antimicrobienne.

Mice with FVB-derived sequence on chromosome 17 succumb to disseminated virus infection due to aberrant NK cell and T cell responses.

Zoonotic arenavirus infections can result in viral hemorrhagic disease, characterized by platelet loss, petechia, and multi-organ injury. The mechanisms governing these outcomes are likely impacted by virus strain and infection dose, as well as an individual's genetic background and immune constitution. To better understand the processes leading to severe pathogenesis, we compared two strains of inbred mice, C57BL/6J (B6) and FVB/NJ (FVB), that have diametrically opposed outcomes during disseminated lymphocytic choriomeningitis virus (LCMV) infection. Infection caused minimal pathogenesis in B6 mice, whereas FVB mice developed acute hepatitis and perished due, in part, to aberrant NK cell and T cell responses. Susceptible mice showed an outgrowth of cytolytic CD4+ T cells and loss of Treg cells. B6 congenic mice with the FVB allele at a 25Mb locus on chromosome 17 recapitulated FVB pathogenesis upon infection. A locus containing a limited number of variants in immune-related genes greatly impacts survival during infection.

Whole genome sequencing of increased number of azithromycin-resistant Shigella flexneri 1b isolates in Ontario.

Azithromycin (AZM) resistance among Shigella is a major public health concern. Here, we investigated the epidemiology of Shigella flexneri serotype 1b recovered during 2016-2018 in Ontario, to describe the prevalence and spread of AZM resistance. We found that 72.3% (47/65) of cases were AZM-resistant (AZMR), of which 95.7% (45/47) were among males (P < 0.001). Whole-genome based phylogenetic analysis showed three major clusters, and 56.9% of isolates grouped within a single closely-related cluster (0-10 ∆SNP). A single AZMR clonal population was persistent over 3 years and involved 67.9% (36/53) of all male cases, and none reported international travel. In 2018, a different AZMR cluster appeared among adult males not reporting travel. A proportion of isolates (10.7%) with reduced susceptibility to ciprofloxacin (CIP) due to S83L mutation in gyrA were AZM susceptible, and 71.4% reported international travel. Resistance to AZM was due to the acquisition of mph gene-bearing incFII plasmids having > 95% nucleotide similarity to pKSR100. Plasmid-borne resistance limiting treatment options to AZM, ceftriaxone (CRO) and CIP was noted in a single isolate. We characterized AZMR isolates circulating locally among males and found that genomic analysis can support targeted prevention and mitigation strategies against antimicrobial-resistance.

BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance.

Airway mucociliary clearance (MCC) is required for host defense and is often diminished in chronic lung diseases. Effective clearance depends upon coordinated actions of the airway epithelium and a mobile mucus layer. Dysregulation of the primary secreted airway mucin proteins, MUC5B and MUC5AC, is associated with a reduction in the rate of MCC; however, how other secreted proteins impact the integrity of the mucus layer and MCC remains unclear. We previously identified the gene Bpifb1/Lplunc1 as a regulator of airway MUC5B protein levels using genetic approaches. Here, we show that BPIFB1 is required for effective MCC in vivo using Bpifb1 knockout (KO) mice. Reduced MCC in Bpifb1 KO mice occurred in the absence of defects in epithelial ion transport or reduced ciliary beat frequency. Loss of BPIFB1 in vivo and in vitro altered biophysical and biochemical properties of mucus that have been previously linked to impaired MCC. Finally, we detected colocalization of BPIFB1 and MUC5B in secretory granules in mice and the protein mesh of secreted mucus in human airway epithelia cultures. Collectively, our findings demonstrate that BPIFB1 is an important component of the mucociliary apparatus in mice and a key component of the mucus protein network.NEW & NOTEWORTHY BPIFB1, also known as LPLUNC1, was found to regulate mucociliary clearance (MCC), a key aspect of host defense in the airway. Loss of this protein was also associated with altered biophysical and biochemical properties of mucus that have been previously linked to impaired MCC.

Antibiotic Selection and Duration for Catheter-Associated Urinary Tract Infection in Non-Hospitalized Older Adults: A Population-Based Cohort Study.

Background: We sought to evaluate the impact of antibiotic selection and duration of therapy on treatment failure in older adults with catheter-associated urinary tract infection (CA-UTI). Methods: We conducted a population-based cohort study comparing antibiotic treatment options and duration of therapy for non-hospitalized adults aged 66 and older with presumed CA-UTI (defined as an antibiotic prescription and an organism identified in urine culture in a patient with urinary catheterization documented within the prior 90 d). The primary outcome was treatment failure, a composite of repeat urinary antibiotic prescribing, positive blood culture with the same organism, all-cause hospitalization or mortality, within 60 days. We determined the risk of treatment failure accounting for age, sex, comorbidities, and healthcare exposure using log-binomial regression. Results: Of 4,436 CA-UTI patients, 2,709 (61.1%) experienced treatment failure. Compared to a reference of TMP-SMX (61.9% failure), of those treated with fluoroquinolones, 56.3% experienced failure (RR 0.91, 95% CI: 0.85-0.98) and 60.9% of patients treated with nitrofurantoin experienced failure (RR 1.02, 95% CI: 0.94-1.10). Compared to 5-7 days of therapy (treatment failure: 59.4%), 1-4 days was associated with 69.5% failure (RR 1.15, 95% CI: 1.05-1.27), and 8-14 days was associated with a 62.0% failure (RR 1.05, 95% CI: 0.99-1.11). Conclusions: Although most treatment options for CA-UTI have a similar risk of treatment failure, fluoroquinolones, and treatment durations ≥ 5 days in duration appear to be associated with modestly improved clinical outcomes. From a duration of therapy perspective, this study provides reassurance that relatively short courses of 5-7 days may be reasonable for CA-UTI.