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INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. RESULTS: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. CONCLUSIONS: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.
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Bile acids (BAs) are steroid detergents in bile that contribute to the absorption of fats and fat-soluble vitamins while shaping the gut microbiome because of their antimicrobial properties1-4. Here we identify the enzyme responsible for a mechanism of BA metabolism by the gut microbiota involving amino acid conjugation to the acyl-site of BAs, thus producing a diverse suite of microbially conjugated bile acids (MCBAs). We show that this transformation is mediated by acyltransferase activity of bile salt hydrolase (bile salt hydrolase/transferase, BSH/T). Clostridium perfringens BSH/T rapidly performed acyl transfer when provided various amino acids and taurocholate, glycocholate or cholate, with an optimum at pH 5.3. Amino acid conjugation by C. perfringens BSH/T was diverse, including all proteinaceous amino acids except proline and aspartate. MCBA production was widespread among gut bacteria, with strain-specific amino acid use. Species with similar BSH/T amino acid sequences had similar conjugation profiles and several bsh/t alleles correlated with increased conjugation diversity. Tertiary structure mapping of BSH/T followed by mutagenesis experiments showed that active site structure affects amino acid selectivity. These MCBA products had antimicrobial properties, where greater amino acid hydrophobicity showed greater antimicrobial activity. Inhibitory concentrations of MCBAs reached those measured natively in the mammalian gut. MCBAs fed to mice entered enterohepatic circulation, in which liver and gallbladder concentrations varied depending on the conjugated amino acid. Quantifying MCBAs in human faecal samples showed that they reach concentrations equal to or greater than secondary and primary BAs and were reduced after bariatric surgery, thus supporting MCBAs as a significant component of the BA pool that can be altered by changes in gastrointestinal physiology. In conclusion, the inherent acyltransferase activity of BSH/T greatly diversifies BA chemistry, creating a set of previously underappreciated metabolites with the potential to affect the microbiome and human health.
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Aciltransferases , Amidoidrolases , Ácidos e Sais Biliares , Clostridium perfringens , Microbioma Gastrointestinal , Animais , Humanos , Camundongos , Aciltransferases/química , Aciltransferases/metabolismo , Alelos , Amidoidrolases/química , Amidoidrolases/metabolismo , Aminoácidos/metabolismo , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Cirurgia Bariátrica , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Domínio Catalítico , Clostridium perfringens/enzimologia , Clostridium perfringens/metabolismo , Fezes/química , Vesícula Biliar/metabolismo , Microbioma Gastrointestinal/fisiologia , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Ácido Taurocólico/metabolismoRESUMO
Background: Some studies conducted before the Delta and Omicron variant-dominant periods have indicated that influenza vaccination provided protection against COVID-19 infection or hospitalization, but these results were limited by small study cohorts and a lack of comprehensive data on patient characteristics. No studies have examined this question during the Delta and Omicron periods (08/01/2021 to 2/22/2022). Methods: We conducted a retrospective cohort study of influenza-vaccinated and unvaccinated patients in the Corewell Health East(CHE, formerly known as Beaumont Health), Corewell Health West(CHW, formerly known as Spectrum Health) and Michigan Medicine (MM) healthcare system during the Delta-dominant and Omicron-dominant periods. We used a test-negative, case-control analysis to assess the effectiveness of the influenza vaccine against hospitalized SARS-CoV-2 outcome in adults, while controlling for individual characteristics as well as pandameic severity and waning immunity of COVID-19 vaccine. Results: The influenza vaccination has shown to provided some protection against SARS-CoV-2 hospitalized outcome across three main healthcare systems. CHE site (odds ratio [OR]=0.73, vaccine effectiveness [VE]=27%, 95% confidence interval [CI]: [18-35], p<0.001), CHW site (OR=0.85, VE=15%, 95% CI: [6-24], p<0.001), MM (OR=0.50, VE=50%, 95% CI: [40-58], p <0.001) and overall (OR=0.75, VE=25%, 95% CI: [20-30], p <0.001). Conclusion: The influenza vaccine provides a small degree of protection against SARS-CoV-2 infection across our study sites.
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BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).
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BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.
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Clostridioides difficile , Infecções por Clostridium , Microbiota , Adulto , Humanos , Feminino , Idoso , Masculino , Prevalência , Antibacterianos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , RecidivaRESUMO
Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.
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Estudo de Associação Genômica Ampla , Trombose , Humanos , Bancos de Espécimes Biológicos , Hemostasia , Hemorragia/genética , Doenças RarasRESUMO
BACKGROUND: Vancomycin is associated with potential nephrotoxicity and trough concentrations need to be monitored in certain patients. Falsely decreased vancomycin measurement may result in overtreatment and need to be identified promptly by clinicians and pharmacists to avoid toxicities. METHODS AND RESULTS: We report a case of rheumatoid factor-mediated falsely low vancomycin measurement with Abbott particle-enhanced turbidimetric inhibition immunoassay (PETINIA) method. Reanalyzing the sample using an alternative method, removing the interferences using heterophile blocking reagent as well as rheumatoid factor clean-up solution all helped to solve the false results. Results from alternative method and interference studies showed vancomycin concentrations reached toxic concentrations in the patient and administration of the drug was immediately terminated. The patient experienced a transient increase in serum creatinine. CONCLUSIONS: Even though most modern immunoassays use blocking agents to neutralize interfering antibodies such as rheumatoid factor, it is important for health care professionals to understand that occasional interference still occurs due to the heterogeneous nature of rheumatoid factor.
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Fator Reumatoide , Vancomicina , Humanos , Vancomicina/efeitos adversos , Imunoensaio/métodos , Pessoal de Saúde , ImunoturbidimetriaRESUMO
OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.
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COVID-19 , Adulto , Humanos , Estudos Retrospectivos , Glucocorticoides/uso terapêutico , Biomarcadores , Mortalidade HospitalarRESUMO
This prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 adults with obesity. The percent total weight loss for the highest versus the lowest weight loss tertiles (T3 vs. T1) was 17.0 ± 1.3% and 11.1 ± 0.8%, p < 0.001. Serum metabolite alterations specific to T3 at three months included a decrease in methionine sulfoxide concentration as well as alterations to tryptophan and methionine metabolism (p < 0.03). Fecal metabolite changes specific to T3 included a decrease in taurine concentration and perturbations to arachidonic acid metabolism, and taurine and hypotaurine metabolism (p < 0.002). Preoperative metabolites were found to be highly predictive of weight loss outcomes in machine learning algorithms, with an average area under the curve of 94.6% for serum and 93.4% for feces. This comprehensive metabolomics analysis of weight loss outcome differences post-SG highlights specific metabolic alterations as well as machine learning algorithms predictive of weight loss. These findings could contribute to the development of novel therapeutic targets to enhance weight loss outcomes after SG.
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Importance: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. Design, Setting, and Participants: This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. Interventions: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. Main Outcomes and Measures: The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. Results: Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). Conclusions and Relevance: In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. Trial Registration: ClinicalTrials.gov identifier: NCT03183141.
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Clostridioides difficile , Infecções por Clostridium , Microbiota , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/efeitos adversos , Canadá , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/epidemiologiaRESUMO
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoaV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. In randomized clinical trials, patients who were treated with the anti-spike monoclonal antibody bamlanivimab had fewer COVID-19-related hospitalizations or emergency department (ED) visits than the control group. Methods: A retrospective cohort was assembled across a multisite healthcare system between November 20, 2020 and March 31, 2021. Ambulatory COVID-19 patients treated with bamlanivimab (n = 209) were propensity score matched without replacement (1:1) to a pool of 1024 eligible control patients who received similar care without bamlanivimab. The primary endpoint was all-cause mortality or admission at 30 days. Secondary endpoints included hospitalization, critical care admission, oxygenation requirements, and infusion-related reactions. Propensity score matching (PSM) analysis was used to assess the effect of bamlanivimab infusion on the composite endpoint and secondary endpoints. Results: A total of n = 209 matched patients were included in each arm of the study. The absolute standardized difference (stddiff) was calculated and indicated a balance between the groups. Almost all variables had a stddiff of less than 0.10, except for respiratory rate (RR) (stddiff = -0.11). For the primary composite endpoint of the matched cohort, 10.1% (n = 21) of patients in the intervention group were hospitalized or deceased within 30-day postbamlanivimab infusion versus 27.8% (n = 58) in the control group (adjusted odds ratio [aOR]: 0.29, 95% confidence interval [CI]: 0.17 to 0.51, P < .001). Conclusion: Patients with ambulatory COVID-19 who received bamlanivimab in the outpatient setting had a statistically significant reduction on the odds of admission postinfusion. Despite bamlanivimab's lack of efficacy on newer SARS-CoV-2 variants, this study demonstrates that neutralizing monoclonal antibodies can be effective against specific variants. If variant identification becomes a more accessible tool in outpatient centers or EDs, more targeted therapeutic options may be considered.
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Anticorpos Monoclonais , COVID-19 , Humanos , Anticorpos Monoclonais/uso terapêutico , SARS-CoV-2 , Estudos RetrospectivosRESUMO
BACKGROUND: Serologic analysis is an important tool towards assessing the humoral response to COVID-19 infection and vaccination. Numerous serologic tests and platforms are currently available to support this line of testing. Two broad antibody testing categories are point-of-care lateral flow immunoassays and semi-quantitative immunoassays performed in clinical laboratories, which typically require blood collected from a finger-stick and a standard venipuncture blood draw, respectively. This study evaluated the use of dried blood spot (DBS) collections as a sample source for COVID-19 antibody testing using an automated clinical laboratory test system. METHODS: Two hundred and ninety-four participants in the BLAST COVID-19 seroprevalence study (NCT04349202) were recruited at the time of a scheduled blood draw to have an additional sample taken via finger stick as a DBS collection. Using the EUROIMMUN assay to assess SARS-CoV-2 anti-spike IgG status, DBS specimens were tested on 7, 14, 21, and 28 days post- collection and compared to the reference serum sample obtained from a blood draw for the BLAST COVID-19 study. RESULTS: SARS-CoV-2 anti-spike IgG status from DBS collections demonstrated high concordance with serum across all time points (7-28 days). However, the semi-quantitative value from DBS collections was lower on average than that from serum, resulting in increased uncertainty around the equivocal-to-positive analytical decision point. CONCLUSIONS: DBS collections can be substituted for venipuncture when assaying for COVID-19 IgG antibody, with samples being stable for at least 28 days at room temperature. Finger-stick sampling can therefore be advantageous for testing large populations for SARS-CoV-2 antibodies without the need for phlebotomists or immediate processing of samples. We have high confidence in serostaus determination from DBS collections, although the reduced semi-quantitative value may cause some low-level positives to fall into the equivocal or even negative range.
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COVID-19 , Humanos , Anticorpos Antivirais , COVID-19/diagnóstico , Teste Sorológico para COVID-19 , Teste para COVID-19 , Teste em Amostras de Sangue Seco , Imunoglobulina G , Flebotomia , SARS-CoV-2 , Sensibilidade e Especificidade , Estudos SoroepidemiológicosRESUMO
This study examines adverse events and durability of response of SER-109, an investigational microbiome therapeutic comprised of purified Firmicutes spores, compared with placebo for Clostridioides difficile infection.
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Terapia Biológica , Clostridioides difficile , Infecções por Clostridium , Microbiota , Humanos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/terapia , Seguimentos , Recidiva , Terapia Biológica/métodosRESUMO
Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20−25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.
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Background: The prospective identification of patients at high risk for hospital-acquired/ventilator-associated bacterial pneumonia may improve clinical trial feasibility and foster antibacterial development. In a prior study conducted in the United States, clinical criteria were used to prospectively identify these patients; however, these criteria have not been applied in a European population. Methods: Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of 7 European hospitals were prospectively enrolled from June 12 to December 27, 2017. We estimated the proportion of high-risk patients developing pneumonia according to US Food and Drug Administration guidance and a subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, treatment exposures, and pneumonia incidence in a European cohort and a previously described US cohort. Results: Of 888 high-risk patients, 211/888 (24%) were treated for possible pneumonia, and 150/888 (17%) met the Food and Drug Administration definition for hospital-acquired/ventilator-associated bacterial pneumonia. A higher proportion of European patients treated for possible pneumonia met the pneumonia definition (150/211 [71%] vs 537/1464 [37%]; P < .001). Among patients developing pneumonia, a higher proportion of European patients met antibacterial trial eligibility criteria (124/150 [83%] vs 371/537 [69%]; P < .001). Conclusions: Clinical criteria prospectively identified high-risk patients with high rates of pneumonia in the European cohort. Despite higher rates of established risk factors and incident pneumonia, European patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment in the United States.
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Background: Antibody levels against SARS-CoV-2 can be used as an indicator of recent or past vaccination or infection. However, the prognostic value of antibodies targeting the receptor binding protein (anti-RBD) in hospitalized patients is not widely reported. Purpose: Determine prognostic impact of SARS-CoV-2 antibody quantification at the time of admission on clinical outcomes in hospitalized COVID-19 patients. Methods: We conducted a pilot observational study on patients hospitalized with SARS-CoV-2 infection to determine the prognostic impact of antibody quantitation within the first two days of admission. Anti-nucleocapsid IgG (anti-N) and Anti-RBD levels were measured. Anti-RBD level of 500 AU/mL was used as a cutoff to stratify patients. Spearman's rank Coefficient (rs) was used to demonstrate association. Results: Of the 26 patients included, those who were vaccinated more frequently tested positive for Anti-RBD (100% vs 46.2%, P = 0.005) with higher median titer level (623 vs 0, P = 0.011) compared to unvaccinated patients. Anti-N positivity was more frequently seen in unvaccinated patients (53.9% vs 7.7%, P = 0.03). Anti-RBD levels >500 were associated with lower overall hospital length of stay (LOS)(5 vs 10 days, P = 0.046). The analysis employing a Spearman Rank coefficient demonstrated a strong negative correlation between anti-S titer and LOS (rs=-.515, p = 0.007) and a moderate negative correlation with oxygen needs (rs =-.401, p = 0.042). Conclusion: Anti-RBD IgG levels were associated with lower LOS and oxygen needs during hospitalization. Further studies are needed to determine if levels on admission can be used as a prognostic indicator.
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Intelligence in current AI research is measured according to designer-assigned tasks that lack any relevance for an agent itself. As such, tasks and their evaluation reveal a lot more about our intelligence than the possible intelligence of agents that we design and evaluate. As a possible first step in remedying this, this article introduces the notion of "self-concern," a property of a complex system that describes its tendency to bring about states that are compatible with its continued self-maintenance. Self-concern, as argued, is the foundation of the kind of basic intelligence found across all biological systems, because it reflects any such system's existential task of continued viability. This article aims to cautiously progress a few steps closer to a better understanding of some necessary organisational conditions that are central to self-concern in biological systems. By emulating these conditions in embodied AI, perhaps something like genuine self-concern can be implemented in machines, bringing AI one step closer to its original goal of emulating human-like intelligence.
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Introduction: We wanted to characterize the evolution of the COVID-19 pandemic in a typical metropolitan area. Methods: Data were extracted from the Detroit COVID-19 Consortium database for hospitalized COVID-19 patients treated in Southeast Michigan over the 12-month period from March 2020 to February 2021. Demographic and outcomes data were compared to CDC data. Results: A total of 4,775 patients were enrolled during the study period. We divided the pandemic into three phases: Phase-1 (Spring Surge); Phase-2 (Summer Lull); and Phase-3 (Fall Spike). Changes in hydroxychloroquine, remdesivir, corticosteroid, antibiotic and anticoagulant use closely followed publication of landmark studies. Mortality in critically-ill patients decreased significantly from Phase-1 to Phase-3 (60.3% vs. 47.9%, Chisq p=0.0110). Monthly mortality of all hospitalized patients ranged between 14.8% - 21.5% during Phase-1 and 9.7 to 13.4% during Phase 3 (NS). Discussion: The COVID-19 pandemic presented in three unique phases in Southeast Michigan. Medical systems rapidly modified treatment plans, often preceding CDC and NIH recommendations. Despite improved treatment regimens, intubation rates and mortality for hospitalized patients remained elevated. Conclusion: Preventive measures aimed at reducing hospitalizations for COVID-19 should be emphasized.
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BACKGROUND: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. METHODS/RESULTS: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. CONCLUSIONS: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.
Assuntos
Lipodistrofia , Síndrome Metabólica , Obesidade Mórbida , Metilação de DNA , Epigênese Genética , Humanos , Síndrome Metabólica/genética , Obesidade Mórbida/cirurgia , FenótipoRESUMO
BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).