Abstract
Background
Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination ...and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.
Methods
In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.
Results
89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.
Conclusions
Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.
Clinical Trials Registration
NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
In a phase 2 trial, SER-109, an investigational microbiome drug, did not reduce rates of recurrent CDI, despite a previously successful open-label study. Key contributing factors, which led to a redesign of the currently enrolling phase 3 trial, are highlighted.
Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a ...phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.
We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4–10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.
Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.
In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.
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This article is the work product of the Continuous Glucose Monitor and Automated Insulin Dosing Systems in the Hospital Consensus Guideline Panel, which was organized by Diabetes Technology Society ...and met virtually on April 23, 2020. The guideline panel consisted of 24 international experts in the use of continuous glucose monitors (CGMs) and automated insulin dosing (AID) systems representing adult endocrinology, pediatric endocrinology, obstetrics and gynecology, advanced practice nursing, diabetes care and education, clinical chemistry, bioengineering, and product liability law. The panelists reviewed the medical literature pertaining to five topics: (1) continuation of home CGMs after hospitalization, (2) initiation of CGMs in the hospital, (3) continuation of AID systems in the hospital, (4) logistics and hands-on care of hospitalized patients using CGMs and AID systems, and (5) data management of CGMs and AID systems in the hospital. The panelists then developed three types of recommendations for each topic, including clinical practice (to use the technology optimally), research (to improve the safety and effectiveness of the technology), and hospital policies (to build an environment for facilitating use of these devices) for each of the five topics. The panelists voted on 78 proposed recommendations. Based on the panel vote, 77 recommendations were classified as either strong or mild. One recommendation failed to reach consensus. Additional research is needed on CGMs and AID systems in the hospital setting regarding device accuracy, practices for deployment, data management, and achievable outcomes. This guideline is intended to support these technologies for the management of hospitalized patients with diabetes.
Predictable and sustainable engraftment of live biotherapeutic products into the human gut microbiome is being explored as a promising way to modulate the human gut microbiome. We utilize a synbiotic ...approach pairing the infant gut microbe Bifidobacterium longum subspecies infantis (B. infantis) and human milk oligosaccharides (HMO). B. infantis, which is typically absent in adults, engrafts into healthy adult microbiomes in an HMO-dependent manner at a relative abundance of up to 25% of the bacterial population without antibiotic pretreatment or adverse effects. Corresponding changes in metabolites are detected. Germ-free mice transplanted with dysbiotic human microbiomes also successfully engraft with B. infantis in an HMO-dependent manner, and the synbiotic augments butyrate levels both in this in vivo model and in in vitro cocultures of the synbiotic with specific Firmicutes species. Finally, the synbiotic inhibits the growth of enteropathogens in vitro. Our findings point to a potential safe mechanism for ameliorating dysbioses characteristic of numerous human diseases.
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•Co-dosing with HMO enables reversible gut engraftment of B. infantis in healthy adults•The synbiotic is safe and does not require the use of antibiotics for gut engraftment•Synbiotic induces butyrate production in mice colonized with dysbiotic human microbiota•In vivo and in vitro models show beneficial impacts on metabolites and enteropathogens
Button et al. present proof-of-concept data showing that Bifidobacterium infantis, an infant gut microbe, can be reversibly introduced and maintained in healthy adult guts without prior antibiotic treatment if human milk oligosaccharides are provided. Higher colonization levels are achieved in dysbiotic human-microbiota-associated mice with concomitant butyrate production, suggesting therapeutic potential.
Background. Patients with recurrent Clostridium difficile infection (CDI) have a > 60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This ...exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. Methods. Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10⁹ spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10⁸ spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. Results. Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. Conclusions. SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.
Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of ...investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research.
In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP).
Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups.
Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.
The facultative intracellular bacterium Listeria monocytogenes is being developed as a cancer vaccine platform because of its ability to induce potent innate and adaptive immunity. For successful ...clinical application, it is essential to develop a Listeria platform strain that is safe yet retains the potency of vaccines based on wild-type bacteria. Here, we report the development of a recombinant live-attenuated vaccine platform strain that retains the potency of the fully virulent pathogen, combined with a >1,000-fold reduction in toxicity, as compared with wild-type Listeria. By selectively deleting two virulence factors, ActA (ΔactA) and Internalin B (ΔinlB), the immunopotency of Listeria was maintained and its toxicity was diminished in vivo, largely by blocking the direct internalin B-mediated infection of nonphagocytic cells, such as hepatocytes, and the indirect ActA-mediated infection by cell-to-cell spread from adjacent phagocytic cells. In contrast, infection of phagocytic cells was not affected, leaving intact the ability of Listeria to stimulate innate immunity and to induce antigen-specific cellular responses. Listeria ΔactA/ΔinlB-based vaccines were rapidly cleared from mice after immunization and induced potent and durable effector and memory T-cell responses with no measurable liver toxicity. Therapeutic vaccination of BALB/c mice bearing murine CT26 colon tumor lung metastases or palpable s.c. tumors ($>100\ {\rm mm}^{3}$) with recombinant Listeria ΔactA/ΔinlB expressing an endogenous tumor antigen resulted in breaking of self-tolerance and long-term survival. We propose that recombinant Listeria ΔactA/ΔinlB expressing human tumor-associated antigens represents an attractive therapeutic strategy for further development and testing in human clinical trials.
·POE is characterised by cortical thickening relative to EC.·Thickening occurs primarily in nodes of the CCN and DMN.·Interictal psychosis is characterised by cortical thickening in left occipital ...and temporal regions relative to EC.·This was also evident to a lesser extent in postictal psychosis.·A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.
To explore the cortical morphological associations of the psychoses of epilepsy.
Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC; n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10).
POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network; (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall.
The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.
This debate took place at the Association of Social Anthropologists (ASA) conference in Oxford on 21 September 2018, following the model of the Group Debates in Anthropological Theory at the ...University of Manchester (GDAT). It brought together and into confrontation two of anthropology's relatively new sub‐fields (new at least in their current incarnations), namely evolutionary anthropology and the anthropology of morality and/or ethics. Although organized by a social anthropology professional body, the conference organizers – in line with the wishes of the ASA committee at the time of the call for conference proposals (in 2016) – sought to encourage participation from all forms of anthropology, including archaeology. It was therefore fitting that the debate should pose a question that is of interest across the broad spectrum of anthropology and well beyond, highlighting, we hoped, the venerable anthropological ambition to contribute to the resolution of long‐standing and intractable philosophical questions.The proposition, ‘morality is fundamentally an evolved solution to problems of social co‐operation’, encapsulates a theory developed by Oliver Scott Curry, along with colleagues attached to the Institute of Cognitive and Evolutionary Anthropology (ICEA) and (since 2019) the Centre for the Study of Social Cohesion (CSSC) within the School of Anthropology and Museum Ethnography (SAME) in Oxford. This theory, known as ‘morality as co‐operation’ or MAC, seeks to explain morality in a systematic cross‐cultural manner by means of controlled and operationalized comparison (Curry 2016; Curry, Mullins & Whitehouse 2019). It seemed appropriate to ask Oliver to propose the motion and to select his own seconder. As prospective chair of the debate, I approached colleagues who might be interested in opposing the motion from the perspective of the new anthropology of morality, and the idea of the debate began to take shape.1
The neuropsychological profile of patients with psychosis of epilepsy (POE) has received limited research attention. Recent neuroimaging work in POE has identified structural network pathology in the ...default mode network and the cognitive control network. This study examined the neuropsychological profile of POE focusing on cognitive domains subserved by these networks.
Twelve consecutive patients with a diagnosis of POE were prospectively recruited from the Comprehensive Epilepsy Programmes at The Royal Melbourne, Austin and St Vincent's Hospitals, Melbourne, Australia between January 2015 and February 2017. They were compared to 12 matched patients with epilepsy but no psychosis and 42 healthy controls on standardised neuropsychological tests of memory and executive functioning in a case-control design.
Mean scores across all cognitive tasks showed a graded pattern of impairment, with the POE group showing the poorest performance, followed by the epilepsy without psychosis and the healthy control groups. This was associated with significant group-level differences on measures of working memory (p = < 0.01); immediate (p = < 0.01) and delayed verbal recall (p = < 0.01); visual memory (p < 0.001); and verbal fluency (p = 0.02). In particular, patients with POE performed significantly worse than the healthy control group on measures of both cognitive control (p = .005) and memory (p < .001), whereas the epilepsy without psychosis group showed only memory difficulties (delayed verbal recall) compared to healthy controls (p = .001).
People with POE show reduced performance in neuropsychological functions supported by the default mode and cognitive control networks, when compared to both healthy participants and people with epilepsy without psychosis.
•People with psychosis of epilepsy perform cognitively poorer than matched people with epilepsy without psychosis.•These differences are in areas of memory and cognitive control.•These differences correspond to the default mode and cognitive control brain networks.
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