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The objective of this study was to examine whether bone mineral density (BMD) distribution in the mandibular condyle and facial morphology are associated with temporomandibular joint osteoarthritis (TMJ OA) using clinical cone beam computed tomography (CBCT) images.CBCT images of 35 adults (16 male and 19 female) were examined to obtain TMJ OA counts, cephalometric analyses, and histograms of gray values that are proportional to BMD. Mean, standard deviation (SD), and low and high gray values at the 5th and 95th percentiles (LowThe female group had significantly higher values of TMJ OA counts, mean, and SD on the right mandibular condyle, HighComprehensive analysis of BMD distribution in the mandibular condyle can provide useful information for prognosis of TMJ OA.

Neuroendocrine neoplasms (NENs) are rare epithelial tumors with heterogeneous and frequently unpredictable clinical behavior. Available biomarkers are insufficient to guide individual patient prognosis or therapy selection. Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme expressed by neuroendocrine cells that participates in hormone maturation. The objective of this study was to assess the distribution, clinical associations and survival implications of PAM immunoreactivity in primary NENs. Of 109 primary NENs, 7% were PAM-negative, 25% were PAM-low and 68% were PAM-high. Staining intensity was high in small bowel (p = 0.04) and low in stomach (p = 0.004) NENs. PAM staining was lower in higher grade tumors (p

Clostridioides difficile Infection (CDI) is a leading cause of healthcare-associated infections in Canada, affecting the gastrointestinal tract which can lead to fever, abdominal pain, and diarrhea. Effective treatment for patients with Recurrent CDI (rCDI) can be achieved by Fecal Microbiota Transplantation (FMT) by introducing the gut micro-organisms of a healthy person (donor) into the bowel of the affected individual. Research has shown that an increase in the specific bacterial phyla post-FMT may be partly responsible for this gut restoration and elimination of disease. Furthermore, in understanding the key bacteria associated with successful FMT, full treatment plans can be developed for the individual needs of the patient by matching an infected individual with a donor possessing ideal microbiota for the specific patient. This development of precision medicine and more systematic adoption of FMT can be the next step toward more rapid resolution of rCDI.

Background Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660—a standardized microbiota-based investigational live biotherapeutic—and a closely-matched historical control cohort. Methods This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment. Results In this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p Conclusions In this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence. Clinical Trials Registration NCT02589847 (10/28/2015)

The state of many complex systems, such as ecosystems formed by multiple microbial taxa that interact in intricate ways, is often summarized as a probability distribution on the nodes of a weighted network. This paper develops methods for modeling the organization of such data, as well as their Euclidean counterparts, across spatial scales. Using the notion of diffusion distance, we introduce diffusion Frechet functions and diffusion Frechet vectors associated with probability distributions on Euclidean space and the vertex set of a weighted network, respectively. We prove that these functional statistics are stable with respect to the Wasserstein distance between probability measures, thus yielding robust descriptors of their shapes. We provide several examples that illustrate the geometric characteristics of a distribution that are captured by multi-scale Frechet functions and vectors.

Chronic disease management is a grand challenge, both to the patients for optimal management and to the overall health system with cost utilization. Emerging research evidence suggests that Home Health Monitoring (HHM) using home-based, remoting monitoring technologies can improve the patients’ quality of life, self-management, and achieve cost-effectiveness for the health system. How should HHM be introduced and integrated appropriately into the current healthcare delivery pathways to improve patient care and collect evidence of benefits simultaneously? The Knowledge to Action (KTA) framework is an effective approach in the implementation science literature to methodically guide the translation of evidence-based research findings into practice, putting knowledge into practical use. This article examines the use of the seven-step KTA model to address implementation facilitators and barriers of applying HHM in chronic disease management and then focus on its applicability on chronic obstructive pulmonary disease as an example.

Fecal microbiota transplant (FMT) is a safe and effective treatment for recurrent or refractory Clostridioides (Clostridium) difficile infection (RCDI) in the short term. However, there are a paucity of data on long-term durability and safety of FMT. The aim of this study is to determine the long-term efficacy and safety of FMT for RCDI. Ninety-four patients underwent FMT via retention enema for RCDI between 2008 and 2012 and completed a follow-up questionnaire 4 to 8 years following the last FMT. Of these, 32 were unreachable and 37 were deceased; 23 of the remaining 25 participants completed the survey. No CDI recurrences were reported in patients treated with FMT; 12 of the 23 participants (52.2%) received at least one course of non-CDI antibiotic(s). Nine participants (40.9%) received probiotics and 4 (17.4%) received both non-CDI antibiotics and probiotics. All 23 participants rated their overall health compared with pre-FMT. Current health was considered "much better" in 17 patients (73.9%); "somewhat better" in 3 patients (13.0%); and "about the same" in 3 patients (13.0%). A total of 11 participants (47.8%) reported an increase in weight of more than 5 kg (kg) post-FMT and 9 participants (39.1%) reported no change in weight (± 5 kg). Four of the 23 participants (17.4%) reported improvement or resolution (undifferentiated colitis, n = 1; Crohn's disease, n = 2; ulcerative colitis, n = 1) of pre-existing gastrointestinal condition following FMT. Eight of 23 participants (34.8%) experienced new medical condition(s) post-FMT. The long-term efficacy (48-96 months) of FMT for RCDI appears to be durable even after non-CDI antibiotic use. Thirty percent had improvement of their pre-existing medical conditions following FMT; 73.9% reported "much better" overall health following FMT.

Clinical trials evaluate the benefits and harms of medical interventions with the ultimate goal of establishing an evidence-based regimen that contributes to clinical decision making. Physicians benefit greatly from clinical research because it provides a greater understanding of epidemiology and health outcomes, and patients are given opportunities to participate in such trials. In this review, we discuss the challenges of conducting clinical trials investigating rheumatic diseases, including that of recruitment, finding the right trial, designing a budget, and performing a study in a timely manner. If done right, clinical investigation can be particularly rewarding both intellectually and financially.

Background Clostridium difficile infection (CDI) is an important cause of diarrhea and continues to be a major burden within healthcare institutions and in the community. For a small subset of patients with frequently relapsing CDI who do not have access to fecal microbiota transplantation (FMT), or fail FMT, there are no clear treatment recommendations. We review our experience with prolonged oral vancomycin for secondary prophylaxis of relapsing CDI. Methods We performed a retrospective chart review of cases from the C. difficile consultation service at our institution since 2013. The service had three primary physicians providing consultations and performing over 1000 FMTs over the five-year period. Patients with relapsing CDI who were not candidates for FMT, refused, or relapsed after FMT were treated with vancomycin, followed by long-term oral vancomycin at a dose of 125 mg once daily. Results Twenty patients received at least 8 weeks of once-daily oral vancomycin for prophylaxis of relapsing CDI. Patients had a median age of 80 years, and experienced a median of four episodes of CDI prior to long-term vancomycin. Most were female and 75% had received FMT. Only a single case of C. difficile relapse occurred while on long-term vancomycin during 200 patient-months of follow-up. Amongst those who stopped long-term vancomycin, 31% relapsed within 6 weeks. No adverse events were observed. Conclusions For elderly patients with frequently relapsing C. difficile, prolonged vancomycin once daily at a dose of 125 mg orally was effective in preventing further relapse. Vancomycin secondary prophylaxis may be considered in patients who have failed FMT, or in cases where FMT is not available.

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine preference between groups suggest that caffeine may result in compulsive-like intake in a subpopulation of subjects. Further testing is necessary to determine the factors that contribute to differences in caffeine preference and compulsive-like intake.

Computational topologists recently developed a method, called persistent homology to analyze data presented in terms of similarity or dissimilarity. Indeed, persistent homology studies the evolution of topological features in terms of a single index, and is able to capture higher order features beyond the usual clustering techniques. There are three descriptive statistics of persistent homology, namely barcode, persistence diagram and more recently, persistence landscape. Persistence landscape is useful for statistical inference as it belongs to a space of p −integrable functions, a separable Banach space. We apply tools in both computational topology and statistics to DNA sequences taken from Clostridioides difficile infected patients treated with an experimental fecal microbiota transplantation. Our statistical and topological data analysis are able to detect interesting patterns among patients and donors. It also provides visualization of DNA sequences in the form of clusters and loops.

Background Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II)., Subgroup analyses from MODIFY confirmed that prior Clostridium difficile infection (CDI), age ≥65 years, infection with 027/078/244 strain, compromised immunity, and severe CDI are risk factors for recurrent CDI. Bezlotoxumab reduced CDI recurrence in participants with ≥1 risk factor compared with placebo.

Background The first multicentre paediatric randomised-controlled trial (RCT) of faecal microbiota transplant (FMT) in ulcerative colitis (UC) was recently completed in Ontario and Quebec, Canada. The use of FMT in paediatric UC treatment has been limited to small, open-label case series. Unique clinical and patient factors necessitated a paediatric-specific pilot RCT. Our aim was to assess key feasibility measures of conducting an FMT trial in paediatric patients to inform design, and feasibility of larger, future multicentre studies. Methods Patients were randomised (1:1) to receive rectal enemas 2×/week for 6 weeks, followed by a 6-month follow-up period. Enemas contained normal saline (placebo), or RBX2660 (Rebiotix; Roseville, USA), a faecal microbiota preparation of stool from healthy adult donors (active). Patients were eligible for the open-label extension following completion or withdrawal from the placebo arm. Study feasibility was assessed through patient eligibility, recruitment, completion of sample collections, adverse events, and hospitalisations. Results Over 36 months across two tertiary IBD clinics, 48 paediatric patients were screened for participation. 75.0% (36) met eligibility criteria for enrolment and 69.4% (25) participated in the randomised trial. 53.8% (7) of patients randomised to the placebo arm entered the open-label arm. We stratified completion of sample collections by intervention (Weeks 0–6), and follow-up phases of the trial (Weeks 6–30). 75.3% of required bloodwork was obtained during both phases; patient-provided stool samples declined from 76.0% (intervention) to 45% (follow-up). 83.0% (10) reported adverse events in the active arm, and 38.4% (5) in placebo; these were all minor and self-limited (muscle pain, cough, fatigue, etc.). No patients experienced adverse events related to enemas. Five patients experienced serious adverse events: IBD flare (2 active, 1 placebo), and reactivation of C. difficile infection (2 active) (Table 1). Conclusion In this first paediatric RCT of FMT for UC, we established important feasibility data regarding the design of FMT trials in children. Patient acceptance of FMT was high, and well-tolerated with minor, self-limited adverse events, and few serious adverse events. Return-rates of stool samples were low during follow-up; strategies to improve uptake are needed, particularly given the value of microbiome data for analyses. Overall, our study demonstrates strong interest and tolerance among paediatric patients for FMT-based trials. Future studies will build upon our protocol to enhance clinical data on the effects of microbiota-based therapeutics in children.

Background The role of faecal microbiota transplant (FMT) for the treatment of ulcerative colitis (UC) has been reported across 4 randomised-controlled trials (RCT) in adults. Promising data have emerged from small, open-label paediatric case series and case reports but a proper blinded, placebo-controlled RCT has not been described in children. We report results from the first multicentre RCT of FMT in paediatric UC patients, conducted over 36 months in Ontario and Quebec, Canada. Methods We enrolled 25 children, ages 4–17 years old with active UC across two tertiary IBD clinics. Patients had active inflammation and remained on stable doses of medication at entry. Blinded participants received enemas containing healthy donor stool (active) or normal saline (placebo), 2×/week for 6 weeks. Faecal calprotectin (fCal), C-reactive protein (CRP), and paediatric ulcerative colitis activity index (PUCAI) scores were compared between groups during intervention, and at four follow-up time points over 30 weeks. Donor and recipient stools were measured for 16s rRNA and metagenomics analyses. Results In intention-to-treat (ITT) analysis, FMT (n = 13) at 6 weeks was more likely to improve clinical response (OR 9.3, 95% CI [0.7, 122.6]), CRP (OR 4.7, 95% CI [0.8, 28.4]), and fCal (OR 13.3, 95% CI [1.1, 166.4]) from baseline compared with placebo (n = 12). FMT at 30 weeks was also more likely than placebo to improve clinical response, CRP, and fCal (Table 1). In ITT analysis of the open-label arm (n = 7), FMT at 6 weeks and 30 weeks decreased CRP (−42.9%, −28.6%), fCal (−28.6%, −42.9%), and PUCAI score (−14.3%, −42.9%) from baseline. Conclusion Serial FMT enemas containing healthy donor microbiota led to greater improvements in serum and stool inflammatory markers, and rates of clinical response, in paediatric patients with active UC compared with placebo. These improvements largely persisted beyond 6 months after final FMT treatment. This study offers the strongest preliminary evidence, from a blinded, placebo-controlled multicentre RCT for the role of FMT in the management of paediatric UC.

BACKGROUND: Fecal microbiota transplantation (FMT) has demonstrated considerable success in the treatment of Clostridium difficile infection by reducing pathogen burden and correcting microbial dysbiosis in the host. Our lab is part of a team investigating the efficacy of FMT for patients suffering from ulcerative colitis, and we have previously shown preliminary success in using FMT for treatment of patients with ulcerative colitis. Microbial engraftment in fecal transplant studies has been very difficult to demonstrate, especially given the low DNA sequence resolution provided in 16SrRNA amplicon sequencing and the challenges in refinement of the high-quality genomes from metagenomic samples. AIMS: Building a longitudinal comprehensive database of a healthy donor involved in two randomized control trial studies of fecal microbiome transplant for UC patients. Identifying the bacterial genomes, genes, functions, and metabolites that were transferred from a donor to patients with data from before and after FMT. METHODS: We used a culture-enriched metagenomics (CEMG) approach together with other shotgun metagenomic techniques such as assembly and binning to construct high-quality metagenome assembled genomes (MAGs) from a single donor. We compared the presence of MAGs in a single donor at different time points and created a comprehensive DNA sequence library contains functional annotation and taxonomic assignment. The donor database was used to track the engraftment of genes and genome in 8 FMT recipients from our previous randomized control trial using metagenomic mapping for each patient with data from before and after FMT. RESULTS: CEMG approach combined with in silico assembly-based methods allowed us not to only recover the highest number of MAGs refined from a single donor (203 MAGs) but also, we were able to predict novel metabolites, higher number of functional and carbohydrate activities that were not investigated earlier. We were able to predict metagenome assembled genomes, genes, and functions that were not present before FMT but they were detected in high abundance after fecal microbiota transplantation. CONCLUSIONS: The combination of CEMG and direct shotgun sequencing tackles some of the challenges present in the metagenomics analysis, particularly by increasing the number as well as the accuracy of the MAGs. Our novel culture-dependent approach provides higher genomic resolution that can predict bacterial engraftment in fecal microbiota transplantation for patients with ulcerative colitis. FUNDING AGENCIES: CCC, CIHR

Background: Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections (HAI) in the United States and Canada, and incidence rates have increased worldwide in recent decades. Currently, antibiotics are the mainstay treatments for both primary and recurrent CDI, but their efficacy is limited, prompting further therapies to be developed. Aim: This review summarizes current and emerging therapies in CDI management including antibiotics, fecal microbiota transplantation, monoclonal antibodies, spore-based therapies, and vaccinations.

One of the most difficult and misunderstood aspects of systemic lupus erythematosus (SLE) is its management. Here we discuss the role that sleep, exercise, smoking, alcohol, weather, and stress play in the disease activity and symptomatology of SLE patients. Medication adherence and nonsteroidal antiinflammatory drug usage are also discussed.

Objectives Clostridium difficile infection (CDI) is a major public health concern. Treatment with commonly prescribed antibiotics is associated with high rates of recurrence after initial cure. Here, we present the efficacy and safety of surotomycin, an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide, compared with vancomycin, in patients with CDI. Methods In this Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial, participants received surotomycin 125 mg twice daily, surotomycin 250 mg twice daily or vancomycin 125 mg four times daily for 10 days. The primary efficacy outcome was clinical response at end of treatment. The registration number of the study on clinicaltrials.gov is NCT01085591. Results Clinical cure rates were similar among treatment groups (92.4% for surotomycin 125 mg twice daily, 86.6% for surotomycin 250 mg twice daily and 89.4% for vancomycin). Recurrence rates were 27.9% for surotomycin 125 mg twice daily, 17.2% for surotomycin 250 mg twice daily and 35.6% for vancomycin. The lower recurrence rate with surotomycin 250 mg twice daily versus vancomycin was statistically significant (P = 0.035). Recurrence rates were statistically similar between the surotomycin dose groups (P = 0.193). Rates of sustained clinical response at end of study were 66.7% for surotomycin 125 mg twice daily, 70.1% for surotomycin 250 mg twice daily and 56.1% for vancomycin. Incidence of adverse events was similar among treatment arms. Conclusions Recurrence rates of CDI were lower with surotomycin with higher sustained clinical response rates compared with vancomycin, both of which may offer potential clinical benefits.

Pathogenic strains of bacteria are known to cause various infectious diseases and there is a growing demand for molecular probes that can selectively recognize them. Here we report a special DNAzyme (catalytic DNA), RFD‐CD1, that shows exquisite specificity for a pathogenic strain of Clostridium difficile (C. difficile). RFD‐CD1 was derived by an in vitro selection approach where a random‐sequence DNA library was allowed to react with an unpurified molecular mixture derived from this strain of C. difficle, coupled with a subtractive selection strategy to eliminate cross‐reactivities to unintended C. difficile strains and other bacteria species. RFD‐CD1 is activated by a truncated version of TcdC, a transcription factor, that is unique to the targeted strain of C. difficle. Our study demonstrates for the first time that in vitro selection offers an effective approach for deriving functional nucleic acid probes that are capable of achieving strain‐specific recognition of bacterial pathogens.

Purpose of the Review The purpose of this review is to illustrate specific challenges and opportunities in the building of an adult congenital heart disease (ACHD) program and to highlight critical components and important allies. Recent Findings With more than 1.4 million adults with congenital heart disease in the USA alone, access to specialized, compassionate, high-quality comprehensive care requires a shift toward more aggressive expansion of ACHD care, especially in the context of sparse ACHD provider representation in the vast majority of adult medical centers. Summary The effective build of an ACHD program requires measured escalation in management of ACHD complexity matched with cultivation of key resources and clinical services ranging from congenital cardiac surgery and interventional cardiology to acquired heart disease as well as partnerships with non-cardiac specialists. By reframing ACHD care as a shared goal between patients, providers, hospitals, pharmaceutical and device industry, and payers, a potent business model can be built around the developing ACHD program to facilitate acquisition of these key resources.

Fecal microbiota transplantation (FMT) has been investigated as a potential treatment for inflammatory bowel disease (IBD). This review examines current evidence around the efficacy and safety of FMT for patients with IBD. Randomized controlled trials (RCTs) and meta-analyses have suggested that FMT may facilitate clinical and endoscopic remission in patients with active ulcerative colitis (UC). Although the evidence for FMT in Crohn’s disease (CD) is more limited, positive outcomes have been observed in small cohort studies. Most adverse events (AEs) were mild and included transient gastrointestinal symptoms. Serious adverse events (SAEs) did not differ significantly between the FMT and control groups, and a marginal increased rate of IBD flares following FMT was observed. Microbiota analysis following FMT showed increased intestinal bacterial diversity and a shift towards the donor microbial profile in recipients’ stools. FMT for patients with IBD is promising as RCTs have shown the benefit of FMT for UC, although the efficacy of FMT for CD is less clear. Further large and well-designed trials are necessary to resolve critical issues such as the donor selection, the ideal route of administration, duration, frequency of FMT, and the long-term sustained efficacy and safety.

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N

Clostridium difficile infection (CDI) is a potentially fatal illness, especially in the elderly and hospitalized individuals. The recurrence and rates of CDI are increasing. In addition, some cases of CDI are refractory to the currently available antibiotics. The search for improved modalities for the management of primary and recurrent CDI is underway. This review discusses the current antibiotics, fecal microbiota transplantation (FMT) and other options such as immunotherapy and administration of non-toxigenic Clostridium difficile (CD) for the management of both primary and recurrent CDI.

We have made an accidental discovery of an unusual, single-stranded, guanine-rich DNA molecule that is capable of adopting a folded structure in 7 M urea (7MU) known to denature nucleic acid structures. The folding of this molecule requires Na+ and Mg2+ and the folded structure remains stable when subjected to denaturing (7MU) polyacrylamide gel electrophoresis. Results from sequence mutagenesis, DNA methylation, and circular dichroism spectroscopy studies suggest that this molecule adopts an intramolecular guanine-quadruplex structure with 5 layers of guanine tetrads. Our finding indicates that DNA has the ability to create extremely stable structural folds despite its limited chemical repertoire, making it possible to develop DNA-based systems for unconventional applications.

Clostridium difficile infection (CDI) is one of the most frequent causes of healthcare-associated infections, and its rates are also increasing in the community. The management of CDI has become a major challenge, given growing rates of recurrences and failures with standard antibiotic therapy. Mounting evidence suggests that fecal microbiota transplantation (FMT) may be effective; however, as there is a paucity of data with regard to repeat FMT for primary non-response to this treatment, this study examined the outcome of multiple FMTs for recurrent CDI. Case records were reviewed for 94 patients who underwent FMT via retention enema for recurrent or refractory CDI during the period 2008-2012. Demographic information, treatment data, and clinical resolution rates were examined for single FMT and cumulative resolution was assessed for multiple FMTs in the context of ongoing symptoms. The cumulative clinical resolution following four or more FMTs was 86%. When antibiotic therapy was used between FMTs, the clinical resolution rate increased to 92%. There were no reported adverse events and no patients who were cured with FMT had further episodes of CDI at 6-24 months follow-up. Multiple FMTs administered through enemas is an effective, safe, and simple therapy for the management of recurrent or refractory CDI.

Background Multiple recurrent Clostridium difficile (mrCDI) infections pose major challenges to patients and to the healthcare system. mrCDI is associated with multiple, prolonged hospitalizations and significantly higher costs. It can also lead to chronic, severe diarrhea, colectomy, or death. Fecal microbiota transplantation (FMT) is an effective treatment, but its long-term safety remains unknown, and approximately 10% of patients do not respond to multiple FMTs. A 30-day course of fidaxomicin was evaluated for treatment of acute episode of CDI superimposed on mrCDI, including those who did not respond to multiple FMTs. Fidaxomicin was chosen because it disrupts the fecal microbiome less than vancomycin. Methods Twenty-nine adult patients with at least two episodes of recurrent CDI were initiated on fidaxomicin 200 mg when they experienced new episode of CDI (symptoms plus positive for CD toxin gene by polymerase chain reaction). These patients continued with fidaxomicin 200 mg twice daily for 10 days, and 200 mg once daily for 20 additional days in an open-label clinical trial. The primary endpoints were a clinical response at the completion of 30-day course of fidaxomicin and a sustained clinical response at week 8 from the last dose of fidaxomicin. Patient health-related quality of life was evaluated throughout the treatment using the RAND-36 Item Health Survey (copyright© the RAND Corporation). Results Twenty-four of the 29 patients (83%) experienced clinical resolution of CDI-related symptoms at the completion of 30-day fidaxomicin treatment. Twenty-two of the 29 patients had a sustained clinical response with the overall cure rate of 76% (22/29). Eleven of the 29 patients had multiple FMTs and were enrolled into this study as they failed FMTs. Eight of the 11 patients (73%) of these patients had a sustained clinical response. Statistically significant improvements (P < 0.05) in multiple domains of quality of life according to the RAND-36 Item Health Survey were also observed. Conclusion An extended regimen of fidaxomicin is an effective treatment for adults with multiple rCDI and in restoring quality of life, including those who failed FMTs. Disclosures C. Lee, Rebiotix: Board Member and Grant Investigator, Consulting fee and Research grant. Merck: Research Contractor, Research grant. Pfizer: Grant Investigator, Research grant. Seres: Grant Investigator, Grant recipient. P. Kim, Rebiotix: Board Member, Consulting fee.

Background Numerous microbiota-based therapies are being evaluated for prevention of C. difficile infection (rCDI), a public health threat with high recurrence rates associated with the current standard of care. RBX2660, a standardized microbiota-based drug, was efficacious for preventing rCDI in a double-blinded Phase 2b clinical study (PUNCH CD 2). Herein we report the durability of RBX2660 beyond the initial primary clinical end-point of a subsequent Phase 2 open-label study, demonstrating rCDI prevention at 6 months post-treatment. Methods This prospective, multi-center, open-label Phase 2 study enrolled subjects who had experienced either ≥2 recurrences of CDI following standard-of-care antibiotic therapy or ≥2 episodes of severe CDI requiring hospitalization. Participants received up to two doses of RBX2660 delivered via enema with doses 7 days apart. The primary endpoint of the open-label clinical study defined efficacy as absence of CDI at 8 weeks from the last dose. Safety follow-ups and durability assessments occurred via telephone at 3, 6, 12, and 24 months. The study is ongoing, and not all subjects have completed their assessments. Results This study included 149 RBX2660-treated subjects and 110 historical control subjects from 31 and 4 centers, respectively, in the United States and Canada. At 8-weeks post-treatment, RBX2660’s efficacy in preventing rCDI (79.9%; 119/149) was higher than CDI-free rates in the historical control group (51.8%, 57/110; P < 0.001). Of the 119 subjects who were determined to be treatment success at 8 weeks, 117 have data through 6 months, of which 8 were exited for non-CDI reasons. Of those 109 subjects through the 6-month follow-up, 3 (2.8%) had a new CDI beyond 8 weeks after enema. The 6-month long-term CDI-free rate was 97.2% (106/109) (median follow-up: 182 days; mean: 177 days). Conclusion RBX2660, a microbiota-based drug, was efficacious for the prevention of recurrent CDI with long-term durability at 6-months post-treatment; a result consistent with 6-month rCDI prevention reported for the Phase 2b PUNCH CD 2 trial. Long-term follow-up of RBX2660 safety and efficacy 24 months is ongoing. This analysis was funded by Rebiotix Inc., Roseville, MN. Disclosures S. Mische, Rebiotix, Inc.: Employee, Salary. R. Orenstein, Rebiotix, Inc.: Scientific Advisor, Consulting fee. E. R. Dubberke, Rebiotix, Inc.: Scientific Advisor, Consulting fee. S. Khanna, Rebiotix, Inc.: Scientific Advisor, Consulting fee and Research support. G. Hecht, Rebiotix, Inc.: Scientific Advisor, Consulting fee. H. Dupont, Rebiotix, Inc.: Investigator, Research support. C. Lee, Rebiotix, Inc.: Scientific Advisor, Consulting fee. K. Blount, Rebiotix, Inc.: Employee, Salary.

The clinical and economic burden of Clostridium difficile infection (CDI) is significant. Recurrent CDI management has emerged as a major challenge with suboptimal response to standard therapy. Fecal microbiota transplantation (FMT) has been used as a treatment to reconstitute the normal microbial homeostasis and break the cycle of antibiotic agents that may further disrupt the microbiome. Given the lack of randomized-controlled trials (RCTs) and limitations in previous systematic reviews, we aimed to conduct a systematic review with robust methods to determine the efficacy and safety profile of FMT in CDI.An electronic search was conducted using MEDLINE (1946-March 2012), EMBASE (1974-March 2012) and Cochrane Central Register of Controlled Trials (2012). The search strategy was not limited by language. Abstract data were excluded and only completed studies that underwent the full, rigorous peer-review process were included. Studies that used FMT via any delivery modality for laboratory or endoscopically proven CDI with clinical resolution as primary outcome were included. A sample size of 10 or more patients was a further criterion. Elements of the Centre for Reviews and Dissemination checklist and the National Institute of Clinical Excellence quality assessment for case series checklist were employed to determine study quality. Eligibility assessment and data extraction were performed by two independent researchers. Both unweighted pooled resolution rates (UPR) and weighted pooled resolution rates (WPR) were calculated with corresponding 95% confidence intervals (CI) for overall studies, as well as predefined subgroups.Eleven studies with a total of 273 CDI patients treated with FMT were identified; no RCTs were found as none have been published. Two-hundred and forty-five out of 273 patients experienced clinical resolution (UPR 89.7%; WPR 89.1% (95% CI 84 to 93%)). There was no statistically significant heterogeneity between studies (Cochran Q test P=0.13, I(2)=33.7%). A priori subgroup analysis suggested that lower gastrointestinal FMT delivery (UPR 91.4%; WPR 91.2% (95% CI 86 to 95%)) led to a trend towards higher clinical resolution rates than the upper gastrointestinal route (UPR 82.3%; WPR 80.6% (95% CI 69-90%)) (proportion difference of WPR was 10.6% (95% CI -0.6 to 22%)). No difference in clinical outcomes was detected between anonymous vs. patient selected donors. There were no reported adverse events associated with FMT and follow-up was variable from weeks to years.FMT holds considerable promise as a therapy for recurrent CDI but well-designed, RCTs and long-term follow-up registries are still required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated.

Clostridium difficile is a challenging infection that can be difficult to treat with antibiotic therapy. This chapter outlines the processing material for fecal microbiota transplantation (FMT), also known as stool transplant. Fecal transplantations are effective in treating recurrent C. difficile infection (CDI). FMT uses a stool sample collected from a healthy, screened donor to restore healthy microbiota in the colon of a patient with CDI for symptom resolution. Here, we describe a rapid method for FMT preparation that uses inexpensive and disposable materials.

Background. Vancomycin-resistant Enterococcus (VRE) is a major healthcare-associated pathogen and a well known complication among transplant and immunocompromised patients. We report on stool VRE clearance in a post hoc analysis of the Phase 2 PUNCH CD study assessing a microbiota-based drug for recurrent Clostridium difficile infection (CDI). Methods. A total of 34 patients enrolled in the PUNCH CD study received 1 or 2 doses of RBX2660 (microbiota suspension). Patients were requested to voluntarily submit stool samples at baseline and at 7, 30, and 60 days and 6 months after the last administration of RBX2660. Stool samples were tested for VRE using bile esculin azide agar with 6 µg/mL vancomycin and Gram staining. Vancomycin resistance was confirmed by Etest. Results. VRE status (at least 1 test result) was available for 30 patients. All stool samples for 19 patients (63.3%, mean age 61.7 years, 68% female) tested VRE negative. Eleven patients (36.7%, mean age 75.5 years, 64% female) were VRE positive at the first test (baseline or 7-day follow-up). Of these patients, 72.7%, n = 8 converted to negative as of the last available follow-up (30 or 60 days or 6 months). Of the other 3: 1 died (follow-up data not available); 1 patient remained positive at all follow-ups; 1 patient retested positive at 6 months with negative tests during the interim. Conclusions. Although based on a small sample size, this secondary analysis demonstrated the possibility of successfully converting a high percentage of VRE-positive patients to negative in a recurrent CDI population with RBX2660.

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Importance Clostridium difficile infection (CDI) is a major burden in health care and community settings. CDI recurrence is of particular concern because of limited treatment options and associated clinical and infection control issues. Fecal microbiota transplantation (FMT) is a promising, but not readily available, intervention. Objective To determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT. Design, Setting, and Participants Randomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada. Interventions Patients were randomly allocated to receive frozen (n = 114) or fresh (n = 118) FMT via enema. Main Outcomes and Measures The primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events. Noninferiority margin was set at 15%. Results A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population. In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, −1.6% [95% CI, –10.5% to ∞]; P = .01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, –5.2% to ∞]; P Conclusions and Relevance Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea. Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting. Trial Registration clinicaltrials.gov Identifier:NCT01398969

BACKGROUND: Chronic postherniorrhaphy inguinal pain (CPIP) is a complex, major health problem. In the absence of recurrence or meshoma, laparoscopic retroperitoneal triple neurectomy (LRTN) has emerged as an effective surgical treatment of CPIP.METHODS: This prospective pilot study evaluated the neurophysiological and clinical effects of LRTN. Ten consecutive adult CPIP patients with unilateral predominantly neuropathic inguinodynia underwent three comprehensive quantitative sensory testing (QST) assessments (preoperative, immediate postoperative, and late postoperative). Pain severity, health-related function, and sleep quality were assessed over the course of a 6-month follow-up period.RESULTS: QST revealed marked increases in mechanical, pressure, thermal, and pain thresholds in the areas with maximum pain prior to LRTN surgery for the immediate (P < 0.01; mean 160.9 minutes, range 103 to 255 minutes after extubation) and late postoperative (P < 0.05; mean 27.9 days, range 14 to 78 days after surgery) assessments compared to baseline. Wind-up phenomena were eliminated postoperatively. LRTN provided robust group-level improvements of all clinical measures. No preoperative QST variables were found to be predictive of surgical outcomes. The positive change in heat pain threshold (preoperative compared to late postoperative) showed significant positive correlations with improvements of pain scores and function.CONCLUSIONS: LRTN may produce immediate, profound, and consistent positive effects across multiple mechanical, pressure, and thermal QST variables, and marked improvements of clinical outcomes in selected CPIP patients. These data contribute to the understanding of mechanisms involved in the success of LRTN. Large, high-powered studies are warranted to determine whether preoperative or repeated longitudinal QST may guide patient selection and predict effectiveness of LRTN. (Less)

Clostridium difficile is a challenging infection that can be difficult to treat with antibiotic therapy. This chapter outlines the processing material for fecal microbiota transplantation (FMT), also known as stool transplant. Fecal transplantations are effective in treating recurrent C. difficile infection (CDI). FMT uses a stool sample collected from a healthy, screened donor to restore healthy microbiota in the colon of a patient with CDI for symptom resolution. Here, we describe a rapid method for FMT preparation that uses inexpensive and disposable materials.

Background. This analysis examined the efficacy of fidaxomicin versus vancomycin in 406 Canadian patients withClostridium difficileinfection (CDI), based on data from 2 randomized, clinical trials.Methods. Patients received fidaxomicin or vancomycin 1. Patients were assessed for clinical response recurrence of infection and sustained clinical response for 28 days after treatment completion. Patients at increased risk of recurrence were subjected to subgroup analyses.Results. Clinical response rates for fidaxomicin (90.0%) were noninferior to those with vancomycin (92.2%; 95% confidence interval for difference: −7.7, 3.5). However, fidaxomicin-treated patients had lower recurrence (14.4% versus 28.0%,p=0.001) and higher sustained clinical response (77.1% versus 66.3%,p=0.016). Compared with vancomycin, fidaxomicin was associated with lower recurrence rates in all subgroups, reaching statistical significance in patients with age ≥ 65 years (16.0% versus 30.9%,p=0.026), concomitant antibiotic use (16.2% versus 38.7%,p=0.036), and non-BI strains (11.8% versus 28.3%,p=0.004). Higher sustained clinical response rates were observed for fidaxomicin compared with vancomycin in all subgroups; this was statistically significant in the non-BI subgroup (82.8% versus 69.1%,p=0.021).Conclusions. In Canadian patients, fidaxomicin was superior to vancomycin in sustaining clinical response and reducing CDI recurrence.

Background. Vancomycin-resistant Enterococcus (VRE) is a major healthcare-associated pathogen and a well known complication among transplant and immunocompromised patients. We report on stool VRE clearance in a post hoc analysis of the Phase 2 PUNCH CD study assessing a microbiota-based drug for recurrent Clostridium difficile infection (CDI). Methods. A total of 34 patients enrolled in the PUNCH CD study received 1 or 2 doses of RBX2660 (microbiota suspension). Patients were requested to voluntarily submit stool samples at baseline and at 7, 30, and 60 days and 6 months after the last administration of RBX2660. Stool samples were tested for VRE using bile esculin azide agar with 6 µg/mL vancomycin and Gram staining. Vancomycin resistance was confirmed by Etest. Results. VRE status (at least 1 test result) was available for 30 patients. All stool samples for 19 patients (63.3%, mean age 61.7 years, 68% female) tested VRE negative. Eleven patients (36.7%, mean age 75.5 years, 64% female) were VRE positive at the first test (baseline or 7-day follow-up). Of these patients, 72.7%, n = 8 converted to negative as of the last available follow-up (30 or 60 days or 6 months). Of the other 3: 1 died (follow-up data not available); 1 patient remained positive at all follow-ups; 1 patient retested positive at 6 months with negative tests during the interim. Conclusions. Although based on a small sample size, this secondary analysis demonstrated the possibility of successfully converting a high percentage of VRE-positive patients to negative in a recurrent CDI population with RBX2660.

Background Recurrent Clostridum diffcile infection (rCDI) poses major challenges to healthcare providers and patients. Fecal Microbiota Transplantation (FMT) is an effective therapy for rCDI, but the exact mechanism of its efficacy is unknown. Current metagenomics literature indicates that abundance of Bacteroidetes and Firmicutes may protect against CD proliferation and recurrence. However, this is too broad to be useful for developing refined and targeted microbial-specific therapy for rCDI, because the long-term safety of FMT remains unknown. We examined the phylogeny of bacteria pre- and post- FMT to determine the key organisms associated with successful FMT to the genera level. Methods A subset of patient stool samples (n = 35) from a phase 2 study comparing fresh vs. frozen FMT for rCDI was sequenced at four time points: pre-FMT; at day 10; at week 5; and at week 13, following the last FMT. The matching donor stool was sequenced simultaneously with the corresponding patients’ pre- and post-FMT samples. Using the binary outcome to a single FMT as the response, we have developed an in-house machine learning algorithm, Φ-LASSO, to isolate key genera using the bacterial phylogenetic structure. Engraftment was defined as: newly detected operational taxonomic unit (OTUs) in the patient post-FMT, which were present in the donor but undetected in the patient pre-FMT. Augmentation was defined as: non-donor OTUs whose levels substantially increased post-FMT. Figure 1 (below) displays the distribution of engrafted and augmented OTUs at varying thresholds. We observed increases over time points within each threshold level. Results Akkermansia, Blautia and Roseburiaappear to be key genera for successful FMT. The Φ-LASSO fits with consistently positive coefficients, see Figure 2. Conclusion In this preliminary study, using Φ-LASSO, we have shown that specific microbes to the genera level are uniformly present in successful FMT. This information may lead to developing refined and targeted microbial-therapy for rCDI. Figure 1 Observed (a) engraftment of distinct donor OTUs on patients and (b) augmentation of distinct OTUs in patients for day 10 (D10), week 5 (W5), and week 13 (W13) post-treatment. Figure 2 Fitted coefficients for donor OTUs selected by Φ-LASSO. Disclosures All authors: No reported disclosures.

Parathyroid hormone (PTH) secretion is partially regulated by circulating catecholamines. We examined the effect of different anesthetic techniques on intraoperative PTH (IOPTH) levels in patients undergoing parathyroidectomy for primary hyperparathyroidism.We prospectively studied 132 patients divided into 3 anesthetic cohorts: monitored anesthetic care (MAC; n = 45), general anesthesia with laryngeal mask airway (LMA; n = 43), or general endotracheal anesthesia (GETA; n = 39). IOPTH levels were drawn before induction and at defined intervals postinduction.All anesthetic techniques increased IOPTH levels from preinduction to 3 minutes postinduction (MAC, 28%; LMA, 45%; GETA, 65%; P.001). Temporal trends in postinduction IOPTH levels were similar in patients receiving general anesthesia, characterized by a peak effect at 6 minutes. Using a multivariate logistic regression analysis, GETA was7 times more likely to increase the preinduction IOPTH by ≥ 50% at 3 minutes postinduction compared with MAC (P.0001). Using immediate postinduction IOPTH levels in surgical decision making would have led to failed surgery in 2 of 6 patients with multiple gland disease receiving GETA.Preincision IOPTH samples should be drawn before induction to avoid incorporation of potentially misleading anesthetic-related IOPTH elevations into surgical decision making.