SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

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.).

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.

Effect of propofol anesthesia on force application during colonoscopy.

BACKGROUND: Sedation is frequently used during colonoscopy to control patient discomfort and pain. Propofol is associated with a deeper level of sedation than is a combination of a narcotic and sedative hypnotic and, therefore, may be associated with an increase in force applied to the colonoscope to advance and withdraw the instrument. OBJECTIVE: To compare force application to the colonoscope insertion tube during propofol anesthesia and moderate sedation. DESIGN: An observational cohort study of 13 expert and 12 trainee endoscopists performing colonoscopy in 114 patients. Forces were measured by using the colonoscopy force monitor, which is a wireless, handheld device that attaches to the insertion tube of the colonoscope. SETTING: Community ambulatory surgery center and academic gastroenterology training programs. PATIENTS: Patients undergoing routine screening or diagnostic colonoscopy with complete segment force recordings. MAIN OUTCOME MEASUREMENTS: Axial and radial forces and examination time. RESULTS: Axial and radial forces increase and examination time decreases significantly when propofol is used as the method of anesthesia. LIMITATIONS: Small study, observational design, nonrandomized distribution of sedation type and experience level, different instrument type and effect of prototype device on insertion tube manipulation. CONCLUSIONS: Propofol sedation is associated with a decrease in examination time and an increase in axial and radial forces used to advance the colonoscope.

Segmental increases in force application during colonoscope insertion: quantitative analysis using force monitoring technology.

BACKGROUND: Colonoscopy is a frequently performed procedure that requires extensive training and a high skill level. OBJECTIVE: Quantification of forces applied to the external portion of the colonoscope insertion tube during the insertion phase of colonoscopy. DESIGN: Observational cohort study of 7 expert and 9 trainee endoscopists for analysis of colonic segment force application in 49 patients. Forces were measured by using the colonoscopy force monitor, which is a wireless, handheld device that attaches to the insertion tube of the colonoscope. SETTING: Academic gastroenterology training programs. PATIENTS: Patients undergoing routine screening or diagnostic colonoscopy with complete segment force recordings. MAIN OUTCOME MEASUREMENTS: Axial and radial force and examination time. RESULTS: Both axial and radial force increased significantly as the colonoscope was advanced from the rectum to the cecum. Analysis of variance demonstrated highly significant operator-independent differences between segments of the colon (zones) in all axial and radial forces except average torque. Expert and trainee endoscopists differed only in the magnitude of counterclockwise force, average push/pull force rate used, and examination time. LIMITATIONS: Small study, observational design, effect of prototype device on insertion tube manipulation. CONCLUSION: Axial and radial forces used to advance the colonoscope increase through the segments of the colon and are operator independent.

Celiac disease in an urban VA population with iron deficiency: the case against routine duodenal biopsy.

BACKGROUND: Celiac disease is considered an under-recognized cause of iron deficiency. Small intestinal biopsy is proposed to be part of routine evaluation for iron deficiency. AIMS: To determine the prevalence of celiac disease in an urban, mostly male, mostly minority population with iron deficiency. METHODS: Clinical, endoscopic, and pathologic records of veterans who had undergone esophagogastroduodenoscopy (EGD) and duodenal biopsy for iron deficiency at an urban, tertiary care Veterans Affairs Medical Center were reviewed. The yield of positive duodenal biopsies for celiac disease and pre-defined clinically important findings on EGD were calculated. Confounding factors were assessed in multivariate analysis. The main outcome measures were prevalence of celiac disease and prevalence of clinically important findings on upper gastrointestinal endoscopy. RESULTS: The records of 310 veterans were reviewed. Mean age was 63, range 32-91 years old. Most were male (89%) and African-American (73%). Five of 306 small intestinal biopsies were consistent with celiac disease (type 1 lesions), but tissue transglutaminase obtained in four of the patients was normal, making the prevalence of potential celiac disease 0.33% (95% CI: 0.06-1.83%). Fifty of 310 EGDs demonstrated findings that were considered to have a moderate or high probability of producing iron deficiency (16.1, 95% CI: 12.5-20.6%). CONCLUSIONS: The prevalence of celiac disease is low in an urban, predominately male, African-American population with iron deficiency. Routine small intestinal biopsy for celiac disease in similar populations should not be done. EGD remains clinically important.

Characterization of forces applied by endoscopists during colonoscopy by using a wireless colonoscopy force monitor.

BACKGROUND: To perform a colonoscopy, the endoscopist maneuvers the colonoscope through a series of loops by applying force to the insertion tube. Colonoscopy insertion techniques are operator dependent but have never been comprehensively quantified. OBJECTIVE: To determine whether the Colonoscopy Force Monitor (CFM), a device that continually measures force applied to the insertion tube, can identify different force application patterns among experienced endoscopists. DESIGN: Observational study of 6 experienced endoscopists performing routine diagnostic and therapeutic colonoscopy in 30 patients. SETTING: Outpatient ambulatory endoscopy center. PATIENTS: Adult male and female patients between 30 and 75 years of age undergoing routine colonoscopy. INTERVENTIONS: CFM monitoring of force applied to the colonoscope insertion tube during colonoscopy. MAIN OUTCOME MEASUREMENTS: Maximum and mean linear and torque force, time derivative of force, combined linear and torque vector force, and total manipulation time. RESULTS: The CFM demonstrates differences among endoscopists for maximum and average push/pull and mean torque forces, time derivatives of force, combined push/torque force vector, and total manipulation time. Endoscopists could be grouped by force application patterns. LIMITATIONS: Only experienced endoscopists using conscious sedation in the patients were studied. Sample size was 30 patients. CONCLUSIONS: This study demonstrates that CFM allows continuous force monitoring, characterization, and display of similarities and differences in endoscopic technique. CFM has the potential to facilitate training by enabling trainees to assess, compare, and quantify their techniques and progress.

Analysis of Sciellin (SCEL) as a candidate gene in esophageal squamous cell carcinoma.

BACKGROUND: The aim of this study was to investigate whether a candidate gene, Sciellin (SCEL), mapping to the chromosome 13q21-q31 is mutated in esophageal cancer. MATERIALS AND METHODS: The coding region and intron-exon junctions of SCEL were sequenced in 13 esophageal squamous cell cancers and matching normal esophageal samples to detect mutations. RESULTS: Three single nucleotide polymorphisms were detected in SCEL of which two were silent mutations (L640L and H654H) and one missense mutation (R366K). CONCLUSION: Single nucleotide polymorphisms were detected in both matching tumor and normal esophageal tissues but no disease-associated mutations suggesting that SCEL is not a major factor in esophageal squamous cell carcinogenesis.

Information management.

The desire and requirements for information across the continuum of the enterprise are evident, because outcome measures, quality report cards, and financial pressures effect health care contracting. The real or perceived obstacles to having a comprehensive information management solution (the price tag, the compatibility of hardware and software, multiple locations, ownership of the information, and confidentiality) are so daunting that many are loathe to press ahead. The introduction of modern information technology into the AEC requires a systematic stepwise approach working with trusted partners and stable standards. Intelligent investment in these systems results in a more efficient and effective operating environment based on ongoing data monitoring.

Modeling and in vitro experimental validation for kinetics of the colonoscope in colonoscopy.

Colonoscopy is the most sensitive and specific means for detection of colon cancers and polyps. To make colonoscopy more effective several problems must be overcome including: pain associated with the procedure, the risk of perforation, and incomplete intubation colonoscopy. Technically, these problems are the result of loop formation during colonoscopy. Although, several solutions such as modifying the stiffness of the colonoscope, using an overtube and developing image-guided instruments have been introduced to resolve the looping problem, the results of these systems are not completely satisfactory. A new paradigm to overcome loop formation is proposed that is doctor-assistive colonoscopy. In this approach, the endoscopists performance is enhanced by providing using a kinetic model that provides information such as the shape of the scope, direction of the colon and forces exerted within certain sections. It is expected that with the help of this model, the endoscopist would be able to adjust the manipulation to avoid loop formation. In the present studies, the kinetic model is developed and validated using an ex vivo colonoscopy test-bed with a comprehensive kinematic and kinetic data collection. The model utilizes an established colon model based on animal tissue with position tracking sensors, contact force sensors for the intraluminal portion of the scope and a Colonoscopy Force Monitor for the external insertion tube.

Perforation during colonoscopy in endoscopic ambulatory surgical centers.

BACKGROUND: Perforation as a complication of colonoscopy is estimated to occur in 0.01% to 0.3% of procedures, but the frequency in ambulatory settings is unknown. This study determined the number of perforations occurring within a network of endoscopic ambulatory surgery centers. METHODS: A total of 116,000 colonoscopies were performed within one network of 45 endoscopic ambulatory surgery centers in the United States during 1999. All identified perforations were reported to the network clinical director and reviewed by a panel of 3 gastroenterologists. RESULTS: There were 37 (0.03%) perforations; 27 in women and 10 in men. Median patient age was 75 years (range 39-87 years); 18 patients (49%) had diverticular disease and 20 (54%) had a history of pelvic or colonic surgery. Twenty-four (65%) procedures were diagnostic, and 13 (35%) were therapeutic. The most common site of perforation was the sigmoid colon (62%); followed by the ascending colon (16%); cecum, transverse colon, and splenic flexure (11%); and rectum, anastomotic, or unknown (11%). The time to diagnosis ranged from immediate to 72 hours (29 <1 hour, 8 >1 hour). All patients were hospitalized; 35 (95%) underwent exploratory laparotomy, and 2 (5%) were treated conservatively. No patient died. CONCLUSIONS: Reported perforations for procedures performed in endoscopic ambulatory surgery centers occurred most frequently during diagnostic colonoscopy in older woman with a history of surgery or diverticular disease. Reported perforations in endoscopic ambulatory surgery centers were uncommon.