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The design of potent indoleamine 2,3-dioxygenase 1 (IDOl) enzyme inhibitors targeting immunopathic neuroinflammation has emerged as an area of interest for the treatment of Alzheimer's disease (AD); additionally, recent findings on the clinical benefits of antibodies preventing [beta]-amyloid (Aft) aggregation have renewed efforts to discover small molecule anti-aggregants targeting proteopathic protein misfolding. Exploiting an endogenous tryptophan-like scaffold, we describe the design and synthesis of small-molecule inhibitors of both immunopathic and proteopathic processes, thus presenting the possibility of single therapeutics acting simultaneously on multiple AD pathogeneses. Specifically, investigations on compounds that inhibit both IDOl (in human recombinant enzyme, transfected HEK293 cells, and interferon-[gamma] stimulated human microglia assays) and Aft aggregation (in thioflavin-T and biotinylated-A[beta] oligomeric assays) are presented. Five compounds have been identified with high potency against both targets, identifying (E)-3-styryl indoles as useful tool compounds for developing Alzheimer's therapeutics. Brain penetration of these compounds via passive diffusion or active transport was predicted using Blood-Brain Barrier Score and Brain Exposure Efficiency Score calculations, respectively; the effects of efflux (pgp, BCRP), and influx (OCT1, OCT2) transporters were similarly predicted. Structure-activity relationships were rationalised with molecular docking and molecular dynamics simulations, which also provide insights for future lead compound optimisation. Key words: Alzheimer's disease, tryptophan, IDO-1, amyloid-[beta], neuroinflammation, neuroimmunology La conception de puissants inhibiteurs de l'indoleamine 2,3 dioxygenase 1 (IDOl) ciblant la neuro-inflammation immunopathique constitue desormais un nouveau champ d'interet pour le traitement de la maladie d'Alzheimer (alzheimer). En outre, des donnees recentes sur les bienfaits cliniques des anticorps empechant l'agregation de la beta-amyloide (Aft) ont ravive les efforts visant a decouvrir de petites molecules antiagregantes qui ciblent le mauvais repliement proteopathique des proteines. En exploitant une structure endogene de type tryptophane, nous avons concu et synthetise des inhibiteurs a petite molecule qui ciblent a la fois les processus immunopathiques et proteopathiques, ouvrant ainsi la voie a des monotherapies agissant simultanement sur plusieurs processus pathogenes de l'alzheimer. En particulier, nous presentons des experiences portant sur des composes qui inhibent a la fois IDOl (dans des essais avec des enzymes recombinantes humaines, des cellules HEK293 transferees et des microglies humaines stimulees par 1'interferon [gamma]) et l'agregation de l'A[beta] (dans des essais de liaison avec la thioflavine-T et d'inhibition de l'oligomerisation de l'A[beta] biotinylee). Nous avons identifie cinq composes presentant une forte affinite pour les deux cibles, ce qui nous a permis de definir les (E) 3 styrylindoles comme des composes pouvant servir d'outils pour le developpement d'agents therapeutiques contre l'alzheimer. La penetration cerebrale de ces composes par diffusion passive ou transport actif a ete estimee a l'aide de calculs de l'indice penetration de la barriere hematoencephalique (<< Score BBB >>) et de l'indice d'efficacite de l'exposition cerebrale (<< Score BEE >>), respectivement. Les effets des transporteurs d'efflux (P gp, BCRP) et d'influx (OCT1, OCT2) ont ete egalement ete estimes par calculs. Nous avons rationalise les relations structure-activite a l'aide de simulations d'amarrage moleculaire et de dynamique moleculaire, qui fournissent egalement des informations pour roptimisation d'eventuels composes tetes de serie. [Traduit par la Redaction] Mots-cles : maladie d'Alzheimer, tryptophane, IDOl, beta-amyloide, neuro-inflammation, neuro-immunologie, Introduction The neuropathology of Alzheimer's disease (AD) involves the brain's innate and adaptive immune systems, resulting in a complex inflammatory state that involves not only aggregation of [beta]-amyloid (Aft) and [...]

Food and Drug Administration approval of the first microbiome therapies represents a true expansion the treatment paradigm for Clostridioides difficile but raises new questions about the future role of fecal microbiota transplantation. The authors outline the advances in microbiome therapeutic development that have addressed fecal microbiota transplantation's (FMT's) inherent limitations of safety and scalability. The authors also suggest that as microbiome therapeutic development continues for other indications, FMT will likely remain a necessary model of human microbiota dynamics for translational research. [ABSTRACT FROM AUTHOR]

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections. [ABSTRACT FROM AUTHOR]

Companion animals have been shown to carry Clostridioides difficile strains that are similar or identical to strains found in people, and a small number of studies have shown that pets carry genetically identical C. difficile isolates as their owners, suggesting inter‐species transmission. However, the directionality of transmission is ultimately unknown, and the frequency with which animals acquire C. difficile following their owners' infection is unclear. The goal of this study was to assess how often pets belonging to people with C. difficile infection carry genetically related C. difficile isolates. We enrolled pet owners from two medical institutions (University of Pennsylvania Health System (UPHS) and The Ohio State University Wexner Medical Center (OSUWMC)) who had diarrhoea with or without positive C. difficile assays and tested their faeces and their pets' faeces for C. difficile using both anaerobic culture and PCR assays. When microorganisms were obtained from both the owner and pet and had the same toxin profile or ribotype, isolates underwent genomic sequencing. Faecal samples were obtained from a total of 59 humans, 72 dogs and 9 cats, representing 47 complete households (i.e. where a sample was available from the owner and at least one pet). Of these, C. difficile was detected in 30 humans, 10 dogs and 0 cats. There were only two households where C. difficile was detected in both the owner and pet. In one of these households, the C. difficile isolates were of different toxin profiles/ribotypes (A+/B+ / RT 499 from the owner, A‐/B‐ / RT PR22386 from the dog). In the other household, the isolates were genetically identical (one SNP difference). Interestingly, the dog from this household had recently received a course of antibiotics (cefpodoxime and metronidazole). Our findings suggest that inter‐species transmission of C. difficile occurs infrequently in households with human C. difficile infections. [ABSTRACT FROM AUTHOR]

Background Multidrug-resistant organisms (MDROs) frequently contaminate hospital environments. We performed a multicenter, cluster-randomized, crossover trial of 2 methods for monitoring of terminal cleaning effectiveness. Methods Six intensive care units (ICUs) at 3 medical centers received both interventions sequentially, in randomized order. Ten surfaces were surveyed each in 5 rooms weekly, after terminal cleaning, with adenosine triphosphate (ATP) monitoring or an ultraviolet fluorescent marker (UV/F). Results were delivered to environmental services staff in real time with failing surfaces recleaned. We measured monthly rates of MDRO infection or colonization, including methicillin-resistant Staphylococcus aureus , Clostridioides difficile , vancomycin-resistant Enterococcus, and MDR gram-negative bacilli (MDR-GNB) during a 12-month baseline period and sequential 6-month intervention periods, separated by a 2-month washout. Primary analysis compared only the randomized intervention periods, whereas secondary analysis included the baseline. Results The ATP method was associated with a reduction in incidence rate of MDRO infection or colonization compared with the UV/F period (incidence rate ratio [IRR] 0.876; 95% confidence interval [CI], 0.807–0.951; P  = .002). Including the baseline period, the ATP method was associated with reduced infection with MDROs (IRR 0.924; 95% CI, 0.855–0.998; P  = .04), and MDR-GNB infection or colonization (IRR 0.856; 95% CI, 0.825–0.887; P  < .001). The UV/F intervention was not associated with a statistically significant impact on these outcomes. Room turnaround time increased by a median of 1 minute with the ATP intervention and 4.5 minutes with UV/F compared with baseline. Conclusions Intensive monitoring of ICU terminal room cleaning with an ATP modality is associated with a reduction of MDRO infection and colonization. [ABSTRACT FROM AUTHOR]

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Background Ventilator-associated lower respiratory tract infection (VA-LRTI) is common among critically ill patients and has been associated with increased morbidity and mortality. In acute critical illness, respiratory microbiome disruption indices (MDIs) have been shown to predict risk for VA-LRTI, but their utility beyond the first days of critical illness is unknown. We sought to characterize how MDIs previously shown to predict VA-LRTI at initiation of mechanical ventilation change with prolonged mechanical ventilation, and if they remain associated with VA-LRTI risk. Methods We developed a cohort of 83 subjects admitted to a long-term acute care hospital due to their prolonged dependence on mechanical ventilation; performed dense, longitudinal sampling of the lower respiratory tract, collecting 1066 specimens; and characterized the lower respiratory microbiome by 16S rRNA sequencing as well as total bacterial abundance by 16S rRNA quantitative polymerase chain reaction. Results Cross-sectional MDIs, including low Shannon diversity and high total bacterial abundance, were associated with risk for VA-LRTI, but associations had wide posterior credible intervals. Persistent lower respiratory microbiome disruption showed a more robust association with VA-LRTI risk, with each day of (base e) Shannon diversity <2.0 associated with a VA-LRTI odds ratio of 1.36 (95% credible interval, 1.10–1.72). The observed association was consistent across multiple clinical definitions of VA-LRTI. Conclusions Cross-sectional MDIs have limited ability to discriminate VA-LRTI risk during prolonged mechanical ventilation, but persistent lower respiratory tract microbiome disruption, best characterized by consecutive days with low Shannon diversity, may identify a population at high risk for infection and may help target infection-prevention interventions. [ABSTRACT FROM AUTHOR]

Comparative genomics has enabled the identification of genes that potentially evolved de novo from non-coding sequences. Many such genes are expressed in male reproductive tissues, but their functions remain poorly understood. To address this, we conducted a functional genetic screen of over 40 putative de novo genes with testis-enriched expression in Drosophila melanogaster and identified one gene, atlas, required for male fertility. Detailed genetic and cytological analyses showed that atlas is required for proper chromatin condensation during the final stages of spermatogenesis. Atlas protein is expressed in spermatid nuclei and facilitates the transition from histone- to protamine-based chromatin packaging. Complementary evolutionary analyses revealed the complex evolutionary history of atlas. The protein-coding portion of the gene likely arose at the base of the Drosophila genus on the X chromosome but was unlikely to be essential, as it was then lost in several independent lineages. Within the last ~15 million years, however, the gene moved to an autosome, where it fused with a conserved non-coding RNA and evolved a non-redundant role in male fertility. Altogether, this study provides insight into the integration of novel genes into biological processes, the links between genomic innovation and functional evolution, and the genetic control of a fundamental developmental process, gametogenesis. Author summary: Genomes are in flux, as genes are constantly added and lost throughout evolution. New genes were once thought to arise almost exclusively via the modification or duplication of existing genes. Recently, however, interest has grown in alternative modes of new gene origination, such as de novo evolution from genetic material that previously did not encode proteins. Many de novo genes are expressed in male reproductive tissues, but their significance for fertility is not well understood. We screened likely de novo genes expressed in the Drosophila testis for reproductive roles and found one gene, atlas, essential for male fertility. We leveraged genetic and cell biological experiments to investigate roles for Atlas protein in reproduction and found that it is required during sperm development for proper packaging of DNA in the sperm nucleus. Evolutionary analyses of this gene revealed a complicated history, including loss in some lineages, movement between chromosomes, and fusion with a non-protein-coding gene. Studying both the functions and evolutionary histories of new proteins illustrates how they might evolve critical roles in biological processes despite their relative novelty. Furthermore, the study of atlas identifies an essential genetic player in the fly testis, an important model system for understanding how gametes are produced. [ABSTRACT FROM AUTHOR]

Objective: Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients. Methods: Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication. Results: Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species‐level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3‐ANCA levels (adjusted P = 0.02). Conclusion: In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA. [ABSTRACT FROM AUTHOR]

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) has been used to estimate quantitative viral load, with the goal of targeting isolation precautions for individuals with coronavirus disease 2019 (COVID-19) and guiding public health interventions. However, variability in specimen quality can alter the Ct values obtained from SARS-CoV-2 clinical assays. We sought to define how variable nasopharyngeal (NP) swab quality impacts clinical SARS-CoV-2 test sensitivity. Methods We performed amplification of a human gene target (β-actin) in parallel with a clinical RT-PCR targeting the SARS-CoV-2 ORF1ab gene for 1282 NP specimens collected from patients with clinical concern for COVID-19. We evaluated the relationship between NP specimen quality, characterized by late Ct values for the human gene target β-actin Ct, and the probability of SARS-CoV-2 detection via logistic regression, as well as the linear relationship between SARS-CoV-2 and β-actin Ct. Results Low-quality NP swabs are less likely to detect SARS-CoV-2 (odds ratio, 0.607 [95% credible interval {CrI},.487–.753]). We observed a positive linear relationship between SARS-CoV-2 and β-actin Ct values (slope, 0.181 [95% CrI,.097–.264]), consistent with a reduction in detection of 0.181 cycles for each additional cycle of the β-actin target. COVID-19 disease severity was not associated with β-actin Ct values. Conclusions Variability in NP specimen quality significantly impacts the performance of clinical SARS-CoV-2 assays, and caution should be taken when interpreting quantitative SARS-CoV-2 Ct results. If unrecognized, low-quality NP specimens, which are characterized by a low level of amplifiable human DNA target, may limit the successful application of SARS-CoV-2 Ct values to direct infection control and public health interventions. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 RNA was detected on 32.1% of all surfaces in COVID-19 patient rooms of an acute-care hospital following terminal cleaning. • The prevalence of SARS-CoV-2 RNA contamination was highest among floor surfaces (78.7%). • Odds of SARS-CoV-2 surface contamination increased with month. We evaluated the effect of terminal cleaning on SARS-CoV-2 RNA contamination of COVID-19 isolation rooms in an acute care hospital. SARS-CoV-2 RNA was detected on 32.1% of room surfaces after cleaning; the odds of contamination increased with month. The prevalence of elevated high-touch surface contamination was lower in terminally cleaned rooms than patient-occupied rooms. [ABSTRACT FROM AUTHOR]

In people, colonization with Clostridioides difficile, the leading cause of antibiotic-associated diarrhea, has been shown to be associated with distinct gut microbial features, including reduced bacterial community diversity and depletion of key taxa. In dogs, the gut microbiota features that define C. difficile colonization are less well understood. We sought to define the gut microbiota features associated with C. difficile colonization in puppies, a population where the prevalence of C. difficile has been shown to be elevated, and to define the effect of puppy age and litter upon these features and C. difficile risk. We collected fecal samples from weaned (n = 27) and unweaned (n = 74) puppies from 13 litters and analyzed the effects of colonization status, age and litter on microbial diversity using linear mixed effects models. Colonization with C. difficile was significantly associated with younger age, and colonized puppies had significantly decreased bacterial community diversity and differentially abundant taxa compared to non-colonized puppies, even when adjusting for age. C. difficile colonization remained associated with decreased bacterial community diversity, but the association did not reach statistical significance in a mixed effects model incorporating litter as a random effect. Even though litter explained a greater proportion (67%) of the variability in microbial diversity than colonization status, we nevertheless observed heterogeneity in gut microbial community diversity and colonization status within more than half of the litters, suggesting that the gut microbiota contributes to colonization resistance against C. difficile. The colonization of puppies with C. difficile has important implications for the potential zoonotic transfer of this organism to people. The identified associations point to mechanisms by which C. difficile colonization may be reduced. [ABSTRACT FROM AUTHOR]

Objectives: Sepsis is associated with high early and total in-hospital mortality. Despite recent revisions in the diagnostic criteria for sepsis that sought to improve predictive validity for mortality, it remains difficult to identify patients at greatest risk of death. We compared the utility of nine biomarkers to predict mortality in subjects with clinically suspected bacterial sepsis.Design: Cohort study.Setting: The medical and surgical ICUs at an academic medical center.Subjects: We enrolled 139 subjects who met two or more systemic inflammatory response syndrome (systemic inflammatory response syndrome) criteria and received new broad-spectrum antibacterial therapy.Interventions: We assayed nine biomarkers (α-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin, serum amyloid A, serum amyloid P, and tissue plasminogen activator) at onset of suspected sepsis and 24, 48, and 72 hours thereafter. We compared biomarkers between groups based on both 14-day and total in-hospital mortality and evaluated the predictive validity of single and paired biomarkers via area under the receiver operating characteristic curve.Measurements and Main Results: Fourteen-day mortality was 12.9%, and total in-hospital mortality was 29.5%. Serum amyloid P was significantly lower (4/4 timepoints) and tissue plasminogen activator significantly higher (3/4 timepoints) in the 14-day mortality group, and the same pattern held for total in-hospital mortality (Wilcoxon p ≤ 0.046 for all timepoints). Serum amyloid P and tissue plasminogen activator demonstrated the best individual predictive performance for mortality, and combinations of biomarkers including serum amyloid P and tissue plasminogen activator achieved greater predictive performance (area under the receiver operating characteristic curve > 0.76 for 14-d and 0.74 for total mortality).Conclusions: Combined biomarkers predict risk for 14-day and total mortality among subjects with suspected sepsis. Serum amyloid P and tissue plasminogen activator demonstrated the best discriminatory ability in this cohort. [ABSTRACT FROM AUTHOR]

A substantial proportion of Clostridium difficile infection (CDI) cases recur after completion of antibiotic therapy, and antibiotic cure rates diminish with each recurrence of CDI. Fecal microbiota transplantation (FMT) is an effective therapy for recurrent FMT, which otherwise requires prolonged or indefinite antibiotic treatment. FMT is performed by introducing the fecal microbial community obtained from a healthy donor or pool of donors into the stomach, small intestine, or colon of a patient with CDI. Multiple clinical trials support the usefulness of FMT in treating recurrent CDI, and CDI treatment guidelines now include consideration of FMT at the third CDI recurrence. However, there remain challenges to incorporating FMT into clinical practice. First, methods of fecal bacterial community processing vary, as do methods of FMT administration. Second, the optimal dosing strategy and expected benefit of FMT for refractory CDI, particularly for severe and severe complicated cases, are uncertain. Third, the US Food and Drug Administration (FDA) considers FMT an investigational treatment. Fourth, insurance reimbursement for FMT usually falls short of FMT administration costs. In the setting of rising C difficile incidence and growing evidence for FMT efficacy, the demand for FMT has increased. However, uncertainty surrounding optimal FMT preparation and administration methods, FDA oversight, and insurance reimbursement presently limits the clinical practice of FMT. [ABSTRACT FROM AUTHOR]

Motivation: The variation in community composition between microbiome samples, termed beta diversity, can be measured by pairwise distance based on either presence--absence or quantitative species abundance data. PERMANOVA, a permutation-based extension of multivariate analysis of variance to a matrix of pairwise distances, partitions within-group and between-group distances to permit assessment of the effect of an exposure or intervention (grouping factor) upon the sampled microbiome. Within-group distance and exposure/intervention effect size must be accurately modeled to estimate statistical power for a microbiome study that will be analyzed with pairwise distances and PERMANOVA. Results: We present a framework for PERMANOVA power estimation tailored to marker-gene microbiome studies that will be analyzed by pairwise distances, which includes: (i) a novel method for distance matrix simulation that permits modeling of within-group pairwise distances according to pre-specified population parameters; (ii) a method to incorporate effects of different sizes within the simulated distance matrix; (iii) a simulation-based method for estimating PERMANOVA power from simulated distance matrices; and (iv) an R statistical software package that implements the above. Matrices of pairwise distances can be efficiently simulated to satisfy the triangle inequality and incorporate group-level effects, which are quantified by the adjusted coefficient of determination, omega-squared (ω²). From simulated distance matrices, available PERMANOVA power or necessary sample size can be estimated for a planned microbiome study. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have spilled over from humans to companion and wild animals since the inception of the global COVID-19 pandemic. However, whole genome sequencing data of the viral genomes that infect non-human animal species have been scant. Here, we detected and sequenced a SARS-CoV-2 delta variant (AY.3) in fecal samples from an 11-year-old domestic house cat previously exposed to an owner who tested positive for SARS-CoV-2. Molecular testing of two fecal samples collected 7 days apart yielded relatively high levels of viral RNA. Sequencing of the feline-derived viral genomes showed the two to be identical, and differing by between 4 and 14 single nucleotide polymorphisms in pairwise comparisons to human-derived lineage AY.3 sequences collected in the same geographic area and time period. However, several mutations unique to the feline samples reveal their divergence from this cohort on phylogenetic analysis. These results demonstrate continued spillover infections of emerging SARS-CoV-2 variants that threaten human and animal health, as well as highlight the importance of collecting fecal samples when testing for SARS-CoV-2 in animals. To the authors' knowledge, this is the first published case of a SARS-CoV-2 delta variant in a domestic cat in the United States. [ABSTRACT FROM AUTHOR]

Abstract: In many studies of HIV replication, it is useful to quantify the number of HIV proviruses in cells against a background of unintegrated forms of the HIV DNA. A popular method for doing so involves quantitative PCR using one primer complementary to the HIV long terminal repeat (LTR), and a second primer complementary to a cellular Alu repeat, so that PCR product only forms from templates where a provirus is integrated in the human genome near an Alu repeat. However, several recent studies have identified conditions that alter distributions of HIV integration sites relative to genes. Because Alu repeats are enriched in gene rich regions, this raises the question of whether altered integration site distributions might confound provirus abundance measurements using the Alu-PCR method. Here modified versions of the HIV tethering protein LEDGF/p75 were used to retarget HIV integration outside of transcription units, and show that this has a negligible effect on Alu-PCR quantitation of proviral abundance. Thus altered integration targeting, at least to the degree achieved here, is not a major concern when using the Alu-PCR assay. [Copyright &y& Elsevier]

Background: In June of 2009, the World Health Organization declared the first influenza pandemic of the 21st century, and by July, New York City's New York-Presbyterian Hospital (NYPH) experienced a heavy burden of cases, attributable to a novel strain of the virus (H1N1pdm). Methods and Results: We present the signs in the NYPH electronic health records (EHR) that distinguished the 2009 pandemic from previous seasonal influenza outbreaks via various statistical analyses. These signs include (1) an increase in the number of patients diagnosed with influenza, (2) a preponderance of influenza diagnoses outside of the normal flu season, and (3) marked vaccine failure. The NYPH EHR also reveals distinct age distributions of patients affected by seasonal influenza and the pandemic strain, and via available longitudinal data, suggests that the two may be associated with distinct sets of comorbid conditions as well. In particular, we find significantly more pandemic flu patients with diagnoses associated with asthma and underlying lung disease. We further observe that the NYPH EHR is capable of tracking diseases at a resolution as high as particular zip codes in New York City. Conclusion: The NYPH EHR permits early detection of pandemic influenza and hypothesis generation via identification of those significantly associated illnesses. As data standards develop and databases expand, EHRs will contribute more and more to disease detection and the discovery of novel disease associations. [ABSTRACT FROM AUTHOR]

Summary: The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions. [Copyright &y& Elsevier]

Background Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated and health care–associated diarrhea in humans. Recurrent CDI (R-CDI) occurs in ~20%–30% of patients with CDI and results in increased morbidity, mortality, and hospital costs. Genomic analyses have shown overlap of C. difficile isolates from animals and people, suggesting that a zoonotic reservoir may contribute to recurrence. The objective of this study was to determine whether pet ownership is a risk factor for recurrence of CDI. Methods We conducted a case–control study among patients with recurrent CDI (cases; n = 86) and patients with nonrecurrent CDI (controls; n = 146). Multivariable logistic regression modeling was used to determine the association between recurrence of CDI and pet ownership while accounting for patient-level risk factors. Results Pet ownership was not significantly associated with recurrence of CDI (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.38–2.72; P  = 0.965) among all patients (n = 232). However, among the subset of patients with community-associated or community-onset health care facility–acquired CDI (n = 127), increasing contact with pets was increasingly protective against recurrence: for every point increase in a pet contact score (out of 7 possible points), the odds of recurrence decreased by 14% (OR, 0.86; 95% CI, 0.74–1.00; P  = 0.051). Conclusions Close interactions with pets appear protective against the recurrence of community-acquired CDI. A potential mechanism may involve beneficial contributions to the microbiota of pet owners afflicted with CDI, as has been observed for other conditions such as atopy, obesity, and food allergies. However, more research is needed to understand the interactions between pets, owners, and their microbiota. [ABSTRACT FROM AUTHOR]

Background We evaluated the differential impact of levofloxacin administered for the prophylaxis of bloodstream infections compared with broad-spectrum beta-lactam (BSBL) antibiotics used for the treatment of neutropenic fever on the gut microbiome in patients with hematologic malignancy. Methods Stool specimens were collected from patients admitted for chemotherapy or stem cell transplant in the setting of the evaluation of diarrhea from February 2017 until November 2017. Microbiome characteristics were compared among those exposed to levofloxacin prophylaxis vs those who received BSBL antibiotics. Results Sixty patients were included, most with acute myeloid leukemia (42%) or multiple myeloma (37%). The gut microbiome of patients with BSBL exposure had significantly reduced Shannon's alpha diversity compared with those without (median [interquartile range {IQR}], 3.28 [1.73 to 3.71] vs 3.73 [3.14 to 4.31]; P =.01). However, those with levofloxacin exposure had increased alpha diversity compared with those without (median [IQR], 3.83 [3.32 to 4.36] vs 3.32 [2.35 to 4.02]; P =.03). Levofloxacin exposure was also associated with a trend toward lower risk of dominance of non-Bacteroidetes genera compared with those without levofloxacin exposure (3 [14%] vs 15 [38%]; P =.051). Conclusions The impact of antibiotics on the gut microbiome varies by class, and levofloxacin may disrupt the gut microbiome less than BSBLs in this patient population. [ABSTRACT FROM AUTHOR]