An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).

Tree species explain only half of explained spatial variability in plant water sensitivity.

Spatiotemporal patterns of plant water uptake, loss, and storage exert a first-order control on photosynthesis and evapotranspiration. Many studies of plant responses to water stress have focused on differences between species because of their different stomatal closure, xylem conductance, and root traits. However, several other ecohydrological factors are also relevant, including soil hydraulics, topographically driven redistribution of water, plant adaptation to local climatic variations, and changes in vegetation density. Here, we seek to understand the relative importance of the dominant species for regional-scale variations in woody plant responses to water stress. We map plant water sensitivity (PWS) based on the response of remotely sensed live fuel moisture content to variations in hydrometeorology using an auto-regressive model. Live fuel moisture content dynamics are informative of PWS because they directly reflect vegetation water content and therefore patterns of plant water uptake and evapotranspiration. The PWS is studied using 21,455 wooded locations containing U.S. Forest Service Forest Inventory and Analysis plots across the western United States, where species cover is known and where a single species is locally dominant. Using a species-specific mean PWS value explains 23% of observed PWS variability. By contrast, a random forest driven by mean vegetation density, mean climate, soil properties, and topographic descriptors explains 43% of observed PWS variability. Thus, the dominant species explains only 53% (23% compared to 43%) of explainable variations in PWS. Mean climate and mean NDVI also exert significant influence on PWS. Our results suggest that studies of differences between species should explicitly consider the environments (climate, soil, topography) in which observations for each species are made, and whether those environments are representative of the entire species range.

Quality of life following treatment with intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer.

OBJECTIVES: Studies that focus on the feasibility of using erlotinib plus chemoradiation to treat locally advanced head and neck cancer have given hints of improved survival outcomes compared to chemoradiation alone. However, the influence of this treatment regimen on the quality of life of the patients has not been documented. We conducted a study of this triple combination and now have documented follow-up survival data as well as long-term quality of life (QoL) measures. METHODS: Three sets of QoL questionnaires were given to patients with a diagnosis of head and neck cancer at two time points, pre- and post-treatment, to assess differences in quality of life after receiving chemotherapy with intra-arterial (IA) cisplatin (150 mg/m2), concomitant radiation (70 Gy), and oral erlotinib (150 mg/day). Additionally, patients were followed for a total of 5 years. RESULTS: Treatment had a detrimental effect on appearance, taste, and saliva domain scores in their QoL questionnaires. Nonetheless, fewer patients reported pain and anxiety. SIGNIFICANCE OF RESULTS: The combination of erlotinib with chemoradiation produced similar adverse effects on the QoL scores of patients with head and neck cancer as compared to chemoradiation alone.

Standards for fecal microbiota transplant: Tools and therapeutic advances.

Fecal microbiota transplantation (FMT) has been demonstrated to be efficacious in preventing recurrent Clostridioides difficile (C. difficile) infections, and is being investigated for treatment of several other diseases including inflammatory bowel disease, cancer, obesity, liver disease, and diabetes. To speed up the translation of FMT into clinical practice as a safe and standardized therapeutic intervention, additional evidence-based technical and regulatory guidance is needed. To this end in May of 2022, the International Alliance for Biological Standardization (IABS) and the BIOASTER Microbiology Technology Institute hosted a second webinar to discuss key issues still impeding the advancement and standardization of FMT. The goal of this two-day webinar was to provide a forum for scientific experts to share and discuss data and key challenges with one another. Discussion included a focus on the evaluation of safety, efficacy, clinical trial design, reproducibility and accuracy in obtained microbiome measurements and data reporting, and the potential for standardization across these areas. It also focused on increasing the application potential and visibility of FMT beyond treating C. difficile infections.

Assessment of parental acceptance towards different non-pharmacological behaviour management techniques in pediatric dental care-a cross-sectional study.

It is imperative to manage children with empathy and concern for their well-being in order to carry out any dental procedure smoothly. Owing to the inherent fear of dental operatory, behaviour management of children is an important aspect of pediatric dental care. Many techniques are available to help manage the behaviour of children. It is, however important to educate parents about these techniques and to get their cooperation for these techniques to be used on their children.This study aimed to familiarize the parents with non-pharmacological behavior management techniques and to determine the parental acceptance of such techniques in children seeking dental treatment in specialty care dental units. A total of 303 parents were evaluated through online questionnaires in this research. They were shown videos of randomly selected non-pharmacologic behaviour management techniques including tell-show-do, positive reinforcement, modelling and voice control. Parents were asked to watch the videos and give their response on seven-items inquiring about their acceptance levels regarding the respective techniques. The responses were recorded on a Likert scales ranging from strongly disagree to strongly agree. According to parental acceptance score (PAS), positive reinforcement was the most accepted technique whereas voice control was the least acceptable technique. Majority of the parents were more receptive towards those techniques that involved a healthy and friendly communication between a dentist and the pediatric patient such as, positive reinforcement, tell show do and modelling. Most significantly the people having low socio-economic status (SES) in Pakistan were more acceptable of voice control than people with high SES.

External Validation and Comparison of Clostridioides difficile Severity Scoring Systems.

BACKGROUND: Many models have been developed to predict severe outcomes from Clostridioides difficile infection (CDI). These models are usually developed at a single institution and largely are not externally validated. Our aim in this study was to validate previously published risk scores in a multicenter cohort of patients with CDI. METHODS: This was a retrospective study on 4 inpatient cohorts with CDI from 3 distinct sites: the universities of Michigan (2010-2012 and 2016), Chicago (2012), and Wisconsin (2012). The primary composite outcome was admission to an intensive care unit, colectomy, and/or death attributed to CDI within 30 days of positive testing. Both within each cohort and combined across all cohorts, published CDI severity scores were assessed and compared to each other and the Infectious Diseases Society of America (IDSA) guideline definitions of severe and fulminant CDI. RESULTS: A total of 3646 patients were included for analysis. Including the 2 IDSA guideline definitions, 14 scores were assessed. Performance of scores varied within each cohort and in the combined set (mean area under the receiver operator characteristic curve [AuROC], 0.61; range, 0.53-0.66). Only half of the scores had performance at or better than IDSA severe and fulminant definitions (AuROCs of 0.64 and 0.63, respectively). Most of the scoring systems had more false than true positives in the combined set (mean, 81.5%; range, 0%-91.5%). CONCLUSIONS: No published CDI severity score showed stable, good predictive ability for adverse outcomes across multiple cohorts/institutions or in a combined multicenter cohort.

Baseline Predictors of Longitudinal Changes in Symptom Severity and Quality of Life in Patients With Suspected Gastroparesis.

BACKGROUND & AIMS: Whether gastric emptying tests predict longitudinal outcomes in patients with symptoms of gastroparesis is unclear. We aimed to determine whether baseline gastric emptying tests and gut motility parameters could impact longitudinal symptom(s) and quality of life (QOL) in a prospective, observational cohort study of patients with symptoms of gastroparesis. METHODS: One hundred fifty patients with gastroparesis symptoms underwent simultaneous scintigraphy (GES) and wireless motility capsule (WMC) measurement of gastric emptying and other motility parameters. Patient Assessment of Upper Gastrointestinal Symptoms and Quality of Life were administered at baseline, and 3 and 6 months after testing. Multivariable generalized linear marginal models were fit to determine which baseline parameters predict longitudinal changes in symptoms and QOL. RESULTS: Overall upper GI symptoms and QOL scores were moderate in severity at baseline and significantly improved over 6 months. Clinical variables, including female gender, harder stools by Bristol stool form score, and presence of functional dyspepsia (FD) by Rome III criteria, were predictive of more severe upper GI symptoms. Even after controlling for these clinical factors, delayed gastric emptying by GES or WMC was associated with worse symptom severity and QOL scores. Low gastric and elevated small bowel contractile parameters by WMC were also independently associated with more severe upper GI symptoms and worse QOL scores. CONCLUSIONS: Baseline features, including demographic and clinical variables, delayed gastric emptying and abnormal gastrointestinal contractility, were independent predictors of more severe longitudinal symptoms and worse quality of life outcomes. These factors may help to risk stratify patients and guide treatment decisions. ClinicalTrials.gov no: NCT02022826.

Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas.

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Can prediction scores be used to identify patients at risk of Clostridioides difficile infection?

PURPOSE OF REVIEW: To describe the current state of literature on modeling risk of incident and recurrent Clostridioides difficile infection (iCDI and rCDI), to underscore limitations, and to propose a path forward for future research. RECENT FINDINGS: There are many published risk factors and models for both iCDI and rCDI. The approaches include scores with a limited list of variables designed to be used at the bedside, but more recently have also included automated tools that take advantage of the entire electronic health record. Recent attempts to externally validate scores have met with mixed success. SUMMARY: For iCDI, the performance largely hinges on the incidence, which even for hospitalized patients can be low (often <1%). Most scores fail to achieve high accuracy and/or are not externally validated. A challenge in predicting rCDI is the significant overlap with risk factors for iCDI, reducing the discriminatory ability of models. Automated electronic health record-based tools show promise but portability to other centers is challenging. Future studies should include external validation and consider biomarkers to augment performance.

Exit strategies from lockdowns due to COVID-19: a scoping review.

INTRODUCTION: In response to the ongoing COVID-19 pandemic, countries have adopted various degrees of restrictive measures on people to reduce COVID-19 transmission. These measures have had significant social and economic costs. In the absence of therapeutics, and low vaccination coverage, strategies for a safe exit plan from a lockdown are required to mitigate the transmission and simultaneously re-open societies. Most countries have outlined or have implemented lockdown exit plans. The objective of this scoping review is to (a) identify and map the different strategies for exit from lockdowns, (b) document the effects of these exit strategies, and (c) discuss features of successful exit strategies based on the evidence. METHODS: A five-step approach was used in this scoping review: (a) identifying the research question and inclusion/exclusion criteria; (b) searching the literature using keywords within PubMed and WHO databases; (c) study selection; (d) data extraction; (e) collating results and qualitative synthesis of findings. RESULTS: Of the 406 unique studies found, 107 were kept for full-text review. Studies suggest the post-peak period as optimal timing for an exit, supplemented by other triggers such as sufficient health system capacity, and increased testing rate. A controlled and step-wise exit plan which is flexible and guided by information from surveillance systems is optimal. Studies recommend continued use of non-pharmaceutical interventions such as physical distancing, use of facemasks, and hygiene measures, in different combinations when exiting from a lockdown, even after optimal vaccination coverage has been attained. CONCLUSION: Reviewed studies have suggested adopting a multi-pronged strategy consisting of different approaches depending on the context. Among the different exit strategies reviewed (phase-wise exit, hard exit, and constant cyclic patterns of lockdown), phase-wise exit appears to be the optimal exit strategy.

Evidence for an expanded hypertension care cascade in low- and middle-income countries: a scoping review.

BACKGROUND: With nearly 90% of annual hypertension-related deaths occurring in low- and middle-income countries (LMICs), there is an urgent need to measure the coverage of health services that effectively manage hypertension. However, there is little agreement on how to define effective coverage and the existing hypertension care cascade (hypertension prevalence, percent aware, percent treated, and percent controlled) does not account for the quality of care received by patients. This study reviews definitions of effective coverage and service quality for hypertension management services and proposes an expanded hypertension care cascade to improve measurement of health systems performance. METHODS: A systematic scoping review of literature published in six electronic databases between January 2000 and October 2020 identified studies that defined effective coverage of hypertension management services or integrated dimensions of service quality into population-based estimates of hypertension management in LMICs. Findings informed an expanded hypertension care cascade from which quality-adjusted service coverage can be calculated to approximate effective coverage. RESULTS: The review identified 18 relevant studies, including 6 that defined effective coverage for hypertension management services and 12 that reported a measure of service quality in a population-based study. Based on commonly reported barriers to hypertension management, new steps on the proposed expanded care cascade include (i) population screened, (ii) population linked to quality care, and (iii) population adhering to prescribed treatment. CONCLUSION: There is little consensus on the definition of effective coverage of hypertension management services, and most studies do not describe the quality of hypertension management services provided to populations. Incorporating aspects of service quality to the hypertension care cascade allows for the calculation of quality-adjusted coverage of relevant services, enabling an appropriate measurement of health systems performance through effective coverage.

An uncommon aetiology for a common clinical problem: Primary pericardial mesothelioma.

Mesothelioma is a tumour arising from the mesothelial cells lining the pleura, pericardium, peritoneum, or the tunica vaginalis of testes. Primary pericardial mesothelioma is a rare tumour that can have varied manifestations and survival in patients with malignant pericardial tumours is generally dismal. The role of asbestos in pericardial mesotheliomas is less well established compared to that in pleural or peritoneal mesotheliomas. The prognosis is generally poor with the treatment options available. We present a middle-aged man with large pericardial effusion secondary to primary pericardial mesothelioma with no previous exposure to asbestos.

Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries.

Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average

En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de

Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de

Signal Versus Noise: How to Analyze the Microbiome and Make Progress on Antimicrobial Resistance.

Antimicrobial resistance has become a worldwide medical challenge [1], so impactful that vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) have entered the common vernacular. We have attempted to reduce the selective pressure through antimicrobial stewardship, curtail the spread by identifying and isolating carriers and individuals with symptomatic infection, and treat antibiotic-resistant organisms (AROs) by developing novel antimicrobials. Despite these extraordinary measures, the challenge of AROs continues to grow. The gut microbiome, the ecosystem of microbes (ie, the microbiota) and metabolites present upon and within all humans, is an emerging target for both the risk for colonization and defense against infection with AROs. Here, informed from experiences and successes with understanding the role of the microbiome in mediating risk of Clostridioides difficile infection (CDI), we (1) review our understanding of the risk from ARO acquisition; (2) review our current understanding of the gut microbiome's ability to resist colonization with AROs; (3) describe how experimental model systems can test these initial, global insights to arrive at more granular, mechanistic ones; and (4) suggest a path forward to make further progress in the field.

Changes in the Association Between Diagnostic Testing Method, Polymerase Chain Reaction Ribotype, and Clinical Outcomes From Clostridioides difficile Infection: One Institution's Experience.

BACKGROUND: In Clostridioides difficile infection (CDI), the relationship between clinical, microbial, and temporal/epidemiological trends, disease severity and adverse outcomes is incompletely understood. In a follow-up to our study from 2010-2013, we evaluate stool toxin levels and C. difficile polymerase chain reaction (PCR) ribotypes. We hypothesized that elevated stool toxins and infection with ribotype 027 associate with adverse outcomes. METHODS: In 565 subjects at the University of Michigan with CDI diagnosed by positive testing for toxins A/B by enzyme immunoassay (EIA) or PCR for the tcdB gene, we quantified stool toxin levels via a modified cell cytotoxicity assay (CCA), isolated C. difficile by anaerobic culture, and performed PCR ribotyping. Severe CDI was defined by Infectious Diseases Society of America (IDSA) criteria, and primary outcomes were all-cause 30-day mortality and a composite of colectomy, intensive care unit admission, and/or death attributable to CDI within 30 days. Analyses included bivariable tests and logistic regression. RESULTS: 199 samples were diagnosed by EIA; 447 were diagnosed by PCR. Toxin positivity associated with IDSA severity but not primary outcomes. In 2016, compared with 2010-2013, ribotype 106 newly emerged, accounting for 10.6% of strains, ribotype 027 fell from 16.5% to 9.3%, and ribotype 014-027 remained stable at 18.9%. Ribotype 014-020 associated with IDSA severity and 30-day mortality (P = .001). CONCLUSIONS: Toxin positivity by EIA and CCA associated with IDSA severity but not with subsequent adverse outcomes. The molecular epidemiology of C. difficile has shifted, which may have implications for the optimal diagnostic strategy for and clinical severity of CDI.

Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment.

OBJECTIVES: We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer (HGNMIBC) who had persistent or recurrent disease after prior intravesical therapy with BCG. The primary endpoint was the safety of this combination. The secondary endpoint was clinical activity at three months following BCG treatment. METHODS: Eighteen patients were consented for the study, five of which were screen failures. Six doses of pembrolizumab were administered every 3 weeks over 16 weeks concurrently with six weekly doses of BCG beginning at week 7. Patient safety was evaluated from the time of consent through 30 days following pembrolizumab treatment. Clinical activity was determined using cystoscopy and biopsy of suspicious lesions. RESULTS: Treatment-related adverse events included one grade 4 adverse event (AEs) (adrenal insufficiency). There were nine grade 3 AEs (chest discomfort, pulmonary embolism, arthritis, wrist edema, injection site reaction, bilateral wrist pain, cardiomyopathy, hypokalemia, urinary tract infection). There were 49 grade 1 and 30 grade 2 AEs (88% of AEs). Eleven patients finished the treatment, and two patients died during the study. Of 13 patients treated, nine patients (69%) had no evidence of disease at 3 months following BCG treatment. CONCLUSIONS: We report for the first time that combining BCG and pembrolizumab in treating HGNMIBC is safe allowing complete treatment of most patients. A phase III trial has opened to test the efficacy of this combination in HGNMIBC (KEYNOTE-676).

Association of Household Pets, Common Dietary Factors, and Lifestyle Factors with Clostridium difficile Infection.

BACKGROUND: Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections and is associated with significant morbidity and mortality. Since owning a cat or dog could enrich the gut microbiome, we hypothesized that it would be protective against CDI. AIMS: We conducted a survey study on patients tested for CDI in order to assess whether living in the presence of a pet is associated with a decreased risk of CDI. METHODS: We surveyed subjects aged 18-90 over a 14-month period using a retrospective case-control design. Subjects with CDI were matched by gender and age to patients who tested negative and had no prior history of CDI. A web-based survey was provided to subjects by mail or assisted by phone. Conditional logistic regression was used to assess for associations between CDI and the various risk factors. RESULTS: 205 CDI positive and 205 CDI negative subjects (response rate of 50.2%) were included. After matching for age and sex, living with a cat or dog was not associated with negative CDI testing. Exploratory multivariable modeling identified an unexpected association between positive CDI testing and high meat intake (OR 2.13, 95% CI 1.21-3.77) as well as between positive CDI testing and cat allergies (OR 1.88, 95% CI 1.02-3.46). CONCLUSION: Living with a cat or dog was not associated with negative CDI testing. Several novel risk factors for CDI have been identified including high meat intake and cat allergies.

Non-steroidal anti-inflammatory drugs are not associated with increased risk of Clostridioides difficile infection: A propensity-score-matched case-control study.

Prior research identified an increased risk for Clostridioides difficile infection (CDI) following exposure to certain non-steroidal anti-inflammatory drugs (NSAIDs). We conducted a retrospective case-control study to evaluate the risk for CDI associated with NSAID use. NSAID use was not associated with an increased risk of CDI.

Anti-toxin antibody is not associated with recurrent Clostridium difficile infection.

Clostridium difficile infection (CDI) recurs in ∼20% of patients. Prior studies indicated that antibody responses directed against the C. difficile toxins A and B were potentially associated with lower risk of recurrent CDI. Here we tested the hypothesis that circulating anti-toxin IgG antibody levels associate with reduced risk of recurrent CDI. A cohort study with prospective enrollment and retrospective data abstraction examined antibody levels in 275 adult patients at the University of Michigan with CDI. We developed an enzyme linked immunosorbent assay to detect IgG antibodies against toxin A and toxin B in sera obtained at the time of diagnosis. Logistic regression examined the relationship between antibody levels and recurrence, and sensitivity tests evaluated for follow-up and survivor biases, history of CDI, and PCR ribotype. Follow-up data were available for 174 subjects, of whom 36 (20.7%) had recurrence. Comparing antibody levels vs. recurrence and CDI history, anti-toxin A levels were similar, while anti-toxin B levels had a greater range of values. In unadjusted analysis, detection of anti-toxin A antibodies, but not anti-toxin B antibodies, associated with an increased risk of recurrence (OR 2.71 [1.06, 8.37], P = .053). Adjusting for confounders weakened this association. The results were the same in sensitivity analyses. We observed a borderline increased risk of recurrence in patients positive for anti-toxin A antibodies, and sensitivity analyses showed this was not simply a reflection of prior exposure status. Future studies are needed to assess how neutralizing antibody or levels after treatment associate with recurrence.

Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization.

Clostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the specific impact of aging on immune responses during C. difficile infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during C. difficile infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to C. difficile infection with the antibiotic cefoperazone and then infected with C. difficile strains with varied disease-causing potentials. We observe that the host age and the infecting C. difficile strain influenced the severity of disease associated with infection. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the ceca and colons of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice, with a corresponding decrease in circulating CXCL1, an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe C. difficile infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.