Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial

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

Dismemberment and Toolmark Analysis on Bone: A Microscopic Analysis of the Walls of Cut Marks

Forensic anthropology may be fundamental in gaining important investigative information in cases of dismemberment: a thorough anthropological survey including the micro- and macromorphological and metrical analysis of marks/lesions found in bones and the microscopic search of residues within the lesions can play a crucial role in providing answers to questions often related to causes and modalities of death as well as to dismemberment tools and methods used. In dismemberment cases, in fact, one of the main objectives is to identify sharp tool classes used in the dismemberment and eventually correlate one specific presumed tool with specific cut marks found in bones. But sometimes additional information may be required as described in the case presented here, for which there has been the need to set up a judicial experiment whose results highlighted again the many lacunae still existing in this field and the need to expand research on toolmark analysi

Machine learning-based identification of vulnerability factors for masonry buildings in aggregate: The historicalcentre of casentino hit by the 2009 l'aquila earthquake

Seismic events in Italy and worldwide have highlighted the high vulnerability of unreinforced masonry (URM) structures in small historical centres. A key feature of these settlements is to be mostly composed of buildings in aggregate, i.e., interconnected by a more or less structurally effective connection. The seismic assessment of such buildings is quite debated in the literature and no shared tools procedures are currently available. The difficulty of standardization derives from the fact that structural units can be characterized by multiple features and configurations that determine a vast number of vulnerability factors, whose interdependency is not straightforward to be identified. The paper addresses this issue by combining evidence-based damage data with the potential offered by Machine Learning (ML) technique. Real data are used in combination with state-of-the-art ML algorithms carefully tuned via an advanced statistical procedure for two main purposes. The first one will be able to predict possible URM damages based on the vulnerability factor in both interpolation and extrapolation scenarios. The second purpose of the ML-based techniques will be to predict the most important vulnerability factors in making these predictions, namely to make the ML-based model explainable and informative about the underlying phenomena and not just predictive. The small historic centre of Casentino, hit by the 2009 L'Aquila earthquake, is adopted in the paper as the first test case study. A large amount of data was collected after the earthquake through in-situ surveys made by the Universities of Genova, Catania and Rome. Data include both geometric and structural factors, i.e., the input data supplied to the ML algorithm, as well as the actual seismic damage mechanisms, i.e., the output data expected to be predicted by the ML algorithm. As first application, ML techniques are applied only to data acquired on out-of-plane mechanisms.The study presented in the paper was developed within the research activities carried out in the frame of 2022-2024 ReLUIS Project – WP10 Masonry Structures (Coordinator - Prof. Guido Magenes). This project has been funded by the Italian Department of Civil Protection. Note that the opinions and conclusions presented by the authors do not necessarily reflect those of the funding entity.Ship Design, Production and Operation

85 - SER-287, an Investigational Microbiome Therapeutic, Induces Remission and Endoscopic Improvement in a Placebo-Controlled, Double-Blind Randomized Trial in Patients with Active Mild-to-Moderate Ulcerative Colitis

AbstractBackgroundFaecal microbiota transplants provide proof-of-concept that manipulation of the gut microbiome can provide therapeutic benefits in patients with ulcerative colitis (UC). SER-287, an ecology of Firmicute bacterial spores, is postulated to decrease gut inflammation by modifying the microbiome composition.MethodsWe conducted a phase 1b trial of SER-287 in 58 adults with mild-to-moderate UC. Patients were assigned to 1 of 3 SER-287 treatment arms or placebo. SER-287 treatment arms included 6 days of vancomycin pre-treatment followed by 8 weeks of SER-287 either daily or weekly and placebo pre-treatment followed by weekly SER-287. Efficacy outcomes included remission (total modified Mayo score [TMMS] ≤2 and endoscopic subscore ≤1), endoscopic improvement (decrease in endoscopic subscore ≥1), clinical response (decrease of ≥3 points in TMMS, with EITHER decrease of ≥1 point in rectal bleeding OR absolute rectal bleeding of 0 of 1) and were assessed, along with safety and tolerability of SER-287 by standard safety measures. Microbiome engraftment was longitudinally assessed by whole metagenomic sequencing.Abstract P421 – Figure 1.Remission and endoscopic improvement, intent to treat (ITT) population.ResultsRemission occurred in 40% (6 of 15) receiving vancomycin pre-treatment followed by SER-287 daily (Vanco/SER-287 QD) and in 0% receiving placebo (p = 0.024, see Figure 1). Endoscopic improvement occurred in 40% (6 of 15) in the Vanco/SER-287 QD arm and in 9% (1 of 11) receiving placebo (not significant). The weekly dosing arms had remission and endoscopic improvement rates intermediate between the Vanco/SER-287 QD and PBO arms, consistent with a dose-dependent effect. Engraftment of SER-287 bacteria was greatest in the Vanco/SER-287 QD compared with other SER-287 treatment or placebo arms. Furthermore, SER-287 bacteria were more prevalent across subjects who achieved remission as compared with those who were not remitters. Safety of SER-287 was comparable to placebo. Gastrointestinal (GI) AEs were most frequent; the Vanco/SER-287 QD arm experienced the lowest percentage of GI AEs, likely reflecting decreased UC disease activity.ConclusionsSER-287 daily for 8 weeks was safe and well tolerated and provides a significant effect in induction of remission in active mild-to-moderate UC patients. Microbiome alterations were consistent with a mechanism of action of engraftment preceding a clinical effect. SER-287 may provide a safe and efficacious oral non-immunosuppressive therapy, addressing an unmet medical need in UC, warranting continued clinical development

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

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