Paragangliomas Arising From the Laryngeal Paraganglia: Thyroid and Laryngeal Paragangliomas With Radiology-Pathology Correlation.

Paragangliomas are neuroendocrine tumors that arise from the embryonic neural crest cells of the extra-adrenal chromaffin and non-chromaffin cellular system. Paragangliomas arising from the laryngeal paraganglia, which occur in the thyroid and larynx, are a rare subset of paragangliomas compared to the more common locations of the carotid body, vagale, jugular, and tympanic paragangliomas. The preoperative diagnosis of both thyroid and laryngeal paragangliomas may pose a challenge due to cytological, pathological, and imaging non-specificity that overlaps with many other neoplasms. These lesions may be associated with significant intraoperative bleeding and complicated excision with adherence to nearby structures, including the recurrent laryngeal nerve. This article discusses the imaging appearance, pathological features, clinical and operative considerations and manifestations, and management of head and neck paragangliomas, as seen in two patients at our institution.

Unplanned Return to Hospital After Same Day Oral Cavity Resection: A Dual Institution Study.

OBJECTIVES: Primary objective: describe rates of 30-days unplanned readmission following outpatient resection of oral cavity cancer. Secondary objective: evaluate for patient and treatment factors associated with readmission. METHODS: Retrospective, dual-institution cohort study of 2 tertiary care referral centers involving adult patients undergoing resection of oral cavity cancer with plans for same-day discharge. Consecutive sample of 77 patients included. Primary outcome was unplanned readmission to emergency room or inpatient stay in the 30 days following surgery. Comparison testing was used between return and non-return groups. RESULTS: Among 77 patients treated with outpatient surgery for oral cavity cancer, 19 (25%) returned to the hospital within 30 days. Among the reasons for return, 16 (80%) were directly related to surgery, and 4 (20%) were related to perioperative medical complications not directly related to a surgical site. Among the 25 patients also undergoing sentinel lymph node biopsy with their oral cavity resection, none returned to the hospital for neck-related complications. While most patients could be safely observed and discharged after return to the hospital, 8 patients (10%) required inpatient readmission. No significant differences between return and non-return groups were identified, although there was a trend toward shorter driving distance from hospital for the return group (47.6 miles vs. 69.5 miles, P = 0.097). CONCLUSION: Unplanned return to the hospital following outpatient oral cavity resection is prevalent and primarily driven by postoperative primary resection site concerns. Among patients selected for same day discharge, no definite population at highest risk of unplanned return was identified.

Microvascular reconstruction of medication related osteonecrosis of the head and neck.

BACKGROUND: Medication related osteonecrosis of the jaw (MRONJ) requiring free flap (FF) reconstruction is uncommon with limited reported findings. METHODS: Multicenter, retrospective case series of 49 consecutive adult patients presenting with advanced MRONJ requiring FF reconstruction from 2010 to 2022. Perioperative complications and outcomes were analyzed. RESULTS: Eighty-two percent (n = 40) of cases were of the mandible and 18% (n = 9) were of the maxilla. The mean follow-up was 15 months (±19.6). The majority of FF survived (96%, n = 47). FF reconstructions of the maxilla were more likely to require postoperative debridement (56%, 95% CI [27, 81%] vs. 15%, 95% CI [7, 25%], p = 0.008) or develop intraoral bone exposure (56%, 95% CI [27, 81%] vs. 18%, 95% CI [9, 27%], p = 0.02). Most patients (71%, n = 35) received preoperative antibiotics which was associated with a higher rate of FF survival (100% vs. 86%, 95% CI [60, 96%], p = 0.02) and fewer complications. CONCLUSIONS: Patients undergoing FF reconstruction for MRONJ do well with high rates of FF success. MRONJ of the maxilla have a higher rate of some complications. Preoperative antibiotics correlated with higher FF survival and fewer postoperative complications.

Otolaryngology Applicant Perspectives on In-person and Virtual Residency Interviews.

OBJECTIVE: The objective of this study was to understand applicant perspectives on in-person and virtual otolaryngology residency interviews. STUDY DESIGN: Survey study. SETTING: Otolaryngology residency applicants who were interviewed during 2022-2023. METHODS: Survey sent to all otolaryngology residency applicants who interviewed during the 2022-2023 interview season. RESULTS: A total of 499 applicants were surveyed with 150 responses (30%). Approximately 48.3% of respondents were offered an in-person interview with 78.9% accepting the offer. Of those who did not accept, reasons included not wanting to travel (21.1%) and time conflicts (15.5%). When comparing virtual versus in-person interviews, those who attended virtual interviews were more likely to disagree that they connected with residents (P = .02) and that they had an improved perspective of the program (P = .002). The majority of applicants agreed that virtual interviews are more inclusive and equitable than in-person interviews (70.4%). When asked which interview style applicants would prefer, 63.1% of applicants preferred an in-person interview when compared to virtual with a second look option (29.5%) and virtual (7.4%). Respondents who self-identified as being underrepresented in medicine were less likely to choose in-person as their preferred interview format (P = .01) and were more likely to decline an in-person interview offer due to monetary limitations (P = .04). CONCLUSIONS: Applicants indicated dissatisfaction with connecting with residents and improving their perspective of the program when in a virtual setting. Applicants felt that virtual interviews were more equitable, but that if the barriers to equity were lessened then they would prefer in-person interviews.

Survey of Laboratory Medicine's national response to the HSE cyberattack in the Republic of Ireland.

BACKGROUND: On Friday 14 May 2021, the Health Service Executive (HSE) was subjected to a serious cyberattack on their information technology (IT) infrastructure. Healthcare workers lost access to HSE-provided clinical and non-clinical IT systems, including laboratory systems. AIM: The aim of this national survey was to capture Laboratory Medicine's response across the Republic of Ireland during the HSE cyberattack. METHOD: An electronic survey developed using Microsoft Forms® was emailed on 24 September 2021 to 58 local representatives of the PeriAnalytic and Laboratory Medicine Society (PALMSoc). RESULTS: The survey was sent to 43 clinical laboratories across the Republic of Ireland. A total of 41 responses from 43 laboratories across all laboratory disciplines were received (95% response rate). From these, 55% did not have access to a functioning LIS, with 56% of these not having access to a LIS for greater than 2 weeks. A decrease in specimen requests received during this period was reported by 74% of laboratories, with 32% experiencing a reduction that lasted in excess of one month. Over half of the laboratories (55%) experienced a reduction of > 30% in requests, indicating that clinicians stopped investigating patients (87% reduction in primary care), further escalating the disruption to healthcare. CONCLUSION: The cyberattack burdened the HSE and laboratories at a time when healthcare staffs were coming to terms with the impact of the COVID-19 pandemic. Despite this, the survey confirms the agility of laboratory staff in meeting the demands placed on it during this time.

Outcomes of Head and Neck Free Tissue Transfer in Renal Failure Patients.

OBJECTIVE: To assess if there is increased risk of free flap failure in renal failure patients undergoing head and neck reconstruction. We seek to primarily assess free flap outcomes based on stages of chronic kidney disease (CKD) and secondarily determine increased risk for postoperative complications. METHODS: Retrospective chart review was performed at five tertiary care centers. Patients were identified that had undergone microvascular free flap reconstruction of the head and neck with diagnosis of renal failure, classified as Stage 3 CKD or higher. Demographic data was collected. Outcomes in the postoperative period were examined. RESULTS: Seventy-three patients met inclusion criteria. The average patient age was 69 years with a male predominance (n = 48). The majority of patients had CKD Stage 3 (n = 52). Overall flap failure rate was 12.33% (n = 9, CKD stage 3 = 7.69%, CKD stage 4 = 30%, CKD stage 5 = 18%). There was an increased risk of flap failure on multivariate analysis for CKD stage 4/5 patients when compared to CKD 3 patients (p = 0.0095). When compared to matched controls, there was an increased risk of flap failure in CKD patients (p = 0.01) as well as an increased risk of overall complications (p < 0.0001). CONCLUSIONS: Patients with CKD undergoing head and neck reconstruction are at a higher risk of flap failure and overall complications. When comparing CKD stages there may be increased risk of flap failure in later stages of CKD compared to CKD 3. Appropriate patient counseling is recommended pre-operatively in this patient population with consideration for regional flaps in the appropriate patient. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:688-694, 2024.

Policy education in a research-focused doctoral nursing program: Power as knowing participation in change.

Nurses have moral obligations incurred by membership in the profession to participate knowingly in health policy advocacy. Many barriers have historically hindered nurses from realizing their potential to advance health policy. The contemporary political context sets additional challenges to policy work due to polarization and conflict. Nursing education can help nurses recognize their role in advancing health through political advocacy in a manner that is consistent with disciplinary knowledge and ethical responsibilities. In this paper, the authors describe an exemplar of Elizabeth Barrett's "Power as Knowing Participation in Change" theory as a disciplinary lens within a doctoral nursing health policy course. Barrett (radically) emphasizes "power as freedom" instead of "power as control." This approach is congruent with nursing disciplinary values and enhances awareness of personal freedom and building collaborative relationships in the policy process. The theory was used in concert with other traditional policy content and frameworks from nursing and other disciplines. We discuss the role of nursing ethics viewed as professional responsibility for policy action, an overview of Barrett's theory, and the design of the course. Four student reflections on how the course influenced their thinking about policy advocacy are included. While not specific to policymaking, Barrett's theory provides a disciplinary grounding to increase students' awareness of freedom and choices in political advocacy participation. Our experience suggests that Barrett's work can be fruitful for enhancing nurses' awareness of choices to participate in change across settings.

Guideline-compliant adjuvant chemotherapy for resected high risk oral cavity cancer: Homefield advantage.

PURPOSE: Factors that are associated with failure to receive guideline-compliant adjuvant chemotherapy after resection of high-risk oral cavity cancer are understudied. Here, we performed a retrospective cohort study of surgically treated patients with oral cavity squamous cell carcinoma to determine rates of guideline-compliant adjuvant chemotherapy and to examine patient factors associated with receiving guideline-compliant chemotherapy. STUDY DESIGN: Retrospective cohort. SETTING: Two tertiary care referral centers. METHODS: Patients with resected high-risk oral cavity squamous cell carcinoma and known adjuvant therapy details were included. Extranodal extension or positive margins were considered high-risk features for which adjuvant chemoradiation was indicated. Patient factors were examined to determine associations with receiving on-guidelines treatment. Univariable and multivariable logistic regression were used to determine significance of associations. RESULTS: 75 patients were included. 36 (48 %) patients received guideline-compliant cisplatin. In total, 39 (52 %) patients did not receive guideline-compliant chemotherapy. On multivariable analysis, meeting with a university medical oncologist was significantly associated with the receipt of guideline-compliant cisplatin (OR 6.38, 95 % CI 2.26-20.0, p < 0.001). CONCLUSION: Adherence to on-guidelines treatment can be difficult to achieve in patients with advanced stage head and neck cancer. Meeting with university medical oncology is associated with an increased chance of receiving guideline-compliant chemotherapy.

Perioperative Assessment/Prehabilitation in Larynx Cancer.

Head and neck cancer (HNC) survivorship is increasing, and with it, a shift in treatment practices has occurred. Radical surgical resections for the treatment of HNC have decreased, and organ preservation treatments have increased. Although effective in treating HNC, chemoradiation therapy toxicities can be detrimental to a patient's overall health, nutrition status, and quality of life (QOL). Considering that dysphagia is typically a driving element of dysfunction, speech-language pathologists are vital to the prehabilitation phase. Prehabilitation programs include a variety of components, with the primary goal being to improve functional and QOL outcomes posttreatment.

Longitudinal Analysis of the Intestinal Microbiota among a Cohort of Children in Rural and Urban Areas of Pakistan.

The profile of the intestinal microbiota is known to be altered in malnourished young children in low- and middle-income countries. However, there are limited studies longitudinally evaluating the intestinal microbiota in malnourished young children in resource-limited settings over the first two years of life. In this longitudinal pilot study, we determined the effect of age, residential location, and intervention on the composition, relative abundance, and diversity of the intestinal microbiota in a representative sample of children under 24 months of age with no diarrhea in the preceding 72 h in the urban and rural areas of Sindh, Pakistan nested within a cluster-randomized trial evaluating the effect of zinc and micronutrients on growth and morbidity (ClinicalTrials.gov Identifier: NCT00705445). The major findings were age-related with significant changes in alpha and beta diversity with increasing age. There was a significant increase in the relative abundance of the Firmicutes and Bacteroidetes phyla and a significant decrease in that of the Actinobacteria and Proteobacteria phyla (p < 0.0001). There were significant increases in the relative abundances of the major genera Bifidobacterium, Escherichia/Shigella and Streptococcus (p < 0.0001), and no significant change in the relative abundance of Lactobacillus. Using the LEfSE algorithm, differentially abundant taxa were identified between children in the first and second years of age, between those residing in rural and urban areas, and those who received different interventions at different ages from 3 to 24 months. The numbers of malnourished (underweight, wasted, stunted) or well-nourished children at each age, in each intervention arm, and at urban or rural sites were too small to determine if there were significant differences in alpha or beta diversity or differentially abundant taxa among them. Further longitudinal studies with larger numbers of well-nourished and malnourished children are required to fully characterize the intestinal microbiota of children in this region.

Differential Response to the Course of Cryptosporidium parvum Infection and Its Impact on Epithelial Integrity in Differentiated versus Undifferentiated Human Intestinal Enteroids.

Cryptosporidium is a leading cause of diarrhea and death in young children and untreated AIDS patients and causes waterborne outbreaks. Pathogenic mechanisms underlying diarrhea and intestinal dysfunction are poorly understood. We previously developed stem-cell derived human intestinal enteroid (HIE) models for Cryptosporidium parvum which we used in this study to investigate the course of infection and its effect on intestinal epithelial integrity. By immunofluorescence and confocal microscopy, there was robust infection of undifferentiated and differentiated HIEs in two and three-dimensional (2D, 3D) models. Infection of differentiated HIEs in the 2D model was greater than that of undifferentiated HIEs but lasted only for 3 days, whereas infection persisted for 21 days and resulted in completion of the life cycle in undifferentiated HIEs. Infection of undifferentiated HIE monolayers suggest that C. parvum infects LGR5+ stem cells. Transepithelial electrical resistance measurement of HIEs in the 2D model revealed that infection resulted in decreased epithelial integrity which persisted in differentiated HIEs but recovered in undifferentiated HIEs. Compromised epithelial integrity was reflected in disorganization of the tight and adherens junctions as visualized using the markers ZO-1 and E-cadherin, respectively. Quantitation using the image analysis tools Tight Junction Organizational Rate and Intercellular Junction Organization Quantification, measurement of monolayer height, and RNA transcripts of both proteins by quantitative reverse transcription PCR confirmed that disruption persisted in differentiated HIEs but recovered in undifferentiated HIEs. These models, which more accurately recapitulate human infection, will be useful tools to dissect pathogenic mechanisms underlying diarrhea and intestinal dysfunction in cryptosporidiosis.

Survey of laboratory medicine's national response to the Covid-19 pandemic in the Republic of Ireland.

BACKGROUND: The global SARS-CoV-2 pandemic placed Irish Laboratory Medicine services under sustained and massive strain. Rapid reconfiguration was required to introduce new assays at high capacity for diagnosis and monitoring of COVID-19, while maintaining existing services. AIM: The aim of this national survey was to capture Laboratory Medicine's response across the Republic of Ireland during the first wave of the COVID-19 pandemic. METHODS: An electronic survey developed using Microsoft Forms® was emailed on 5 October 2020 to 53 local representatives of the PeriAnalytic and Laboratory Medicine Society (PALMSoc), reaching 38 separate pathology departments in the country. RESULTS: A total of 45 responses from 38 laboratories were received (72% response rate) representing a range of departments and disciplines. Most laboratories (63%) introduced new tests, and in a time frame of less than 6 weeks (80%). Point-of-care testing (POCT) played a significant role in the response to COVID-19, with almost half of respondents (47%) reporting that additional equipment was introduced. Maintenance of the Quality Management System (QMS) proved challenging, with 60% of respondents indicating that not all aspects were sustained. When asked about changes to staff rostering, 98% of respondents reported that changes were made. All adjustments were made despite staffing challenges; only 18% of respondents described the staffing levels in their department as 100% prior to the onset of the first wave. CONCLUSIONS: This study confirms an agile and resilient response to the COVID-19 pandemic from Ireland's Laboratory Medicine services despite many economic and staffing challenges.

Maxillectomy Reconstruction Revision Using Virtual Surgical Planning and Intraoperative Navigation.

Secondary revision of osseous flap reconstructions of the maxilla can enhance facial symmetry, but can be challenging due to the absence of normal anatomy and landmarks. We report four cases of maxillectomy reconstruction with scapula tip flap employing a novel combined approach with preoperative virtual surgical planning (VSP) and intraoperative navigation (ION) for secondary revision. VSP was employed to superimpose mirrored normal anatomy upon the reconstructed anatomy, and ION used for real-time intraoperative anatomical mapping. VSP and ION can be used to optimize maxillary bony revisions and recontouring, thereby improving anatomic symmetry and funtionality. Laryngoscope, 131:E2655-E2659, 2021.

Making explicit the development of PhD-prepared nurses to steward the discipline.

Leadership is a core curricular element of PhD programs in nursing. Our PhD faculty began a dialogue about being a leader, a steward of the discipline. We asked ourselves: (a) What expertise do PhD prepared nurse needs to begin to steward the discipline? (b) How do faculty engage PhD nursing students to assume responsibility for stewarding the discipline? Lastly, (c) How do we work with PhD nursing students to create their vision for how their work contributes to stewarding the discipline, from doctoral coursework throughout their career? We support the need for PhD graduates to have the skills to generate knowledge, conserve that which is important, and transform by disseminating new knowledge to a broad audience. Examples of nurses stewarding the discipline when pioneering research, critiquing traditional approaches to inquiry or trends in nursing practice, and developing policy, are highlighted along with examples of how PhD nursing students begin to steward the discipline.

Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids.

Antibiotic treatment is a standard therapy for Clostridioides difficile infection, but dysbiosis of the gut microbiota due to antibiotic exposure is also a major risk factor for the disease. Following an initial episode of C. difficile infection, a relentless cycle of recurrence can occur, where persistent treatment-related dysbiosis predisposes the patient to subsequent relapse. This study uses a longitudinal study design to compare the effects of a narrow-spectrum (ridinilazole) or broad-spectrum antibiotic (vancomycin) on intestinal bile acid profiles and their associations with gut bacteria over the course of C. difficile infection treatment. At the end of treatment (day 10), subjects receiving vancomycin showed a nearly 100-fold increase in the ratio of conjugated to secondary bile acids in their stool compared with baseline, whereas subjects receiving ridinilazole maintained this ratio near baseline levels. Correlation analysis detected significant positive associations between secondary bile acids and several Bacteroidales and Clostridiales families. These families were depleted in the vancomycin group but preserved at near-baseline abundance in the ridinilazole group. Enterobacteriaceae, which expanded to a greater extent in the vancomycin group, correlated negatively and positively with secondary and conjugated primary bile acids, respectively. Bile acid ratios at the end of treatment were significantly different between those who recurred and those who did not. These results indicate that a narrow-spectrum antibiotic maintains an intestinal bile acid profile associated with a lowered risk of recurrence.NEW & NOTEWORTHY This is the first study to demonstrate in humans the relationships between Clostridioides difficile antibiotic treatment choice and bile acid metabolism both during therapy and after treatment cessation. The results show a microbiota- and metabolome-preserving property of a novel narrow-spectrum agent that correlates with the agent's favorable sustained clinical response rates compared with broad-spectrum antibiotic treatment.

Parabacteroides distasonis attenuates tumorigenesis, modulates inflammatory markers and promotes intestinal barrier integrity in azoxymethane-treated A/J mice.

Imbalance of the gut microbial community promotes inflammation and colorectal cancer (CRC). Previously, we demonstrated that freeze-dried Parabacteroides distasonis (Pd) suppressed obesity-driven colorectal tumorigenesis in mice. Here, we investigated if Pd could suppress the development of colon tumors in mice independent of obesity. Six-week-old male A/J mice were assigned to receive: (i) chow diet (CTR); (ii) chow with 0.04% wt/wt freeze-dried Pd (Pd-Early) or (iii) chow diet before switching to 0.04% Pd diet (Pd-Late). Mice remained on diet for 25 weeks with the switch for Pd-Late mice occurring after 19 weeks. All mice received 6 weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after 1 week on diet. Colon tumors were observed in 77, 55 and 40% in CTR, Pd-Early and Pd-Late mice, respectively (X2 = 0.047). Colonic expression of toll-like receptor 4, IL-4 and TNF-α was 40% (P < 0.01), 58% (P = 0.05) and 55% (P < 0.001) lower, respectively, in Pd-Early compared with CTR mice. Pd-Late mice displayed a 217% (P = 0.05) and 185% (P < 0.001) increase in colonic IL-10 and TGF-ß expression, respectively, compared with CTR mice and similar increases in protein abundances were detected (47-145%; P < 0.05). Pd-Early and Pd-Late mice both demonstrated increased colonic expression of the tight junction proteins Zonula occludens-1 (P < 0.001) and occludin (P < 0.001) at the transcript (2-3-fold; P < 0.01) and protein level (30-50%; P < 0.05) relative to CTR. Our results support a protective role for Pd in colonic tumorigenesis and maintenance of intestinal epithelial barrier in AOM-treated mice.

Monitoring and capturing patient identification errors in laboratory medicine.

BACKGROUND: Specimen labelling and patient identification are significant contributors to the rate of error in the preanalytical phase of laboratory medicine. This study aimed to investigate the prevalence and nature of preanalytical quality monitoring practices for patient identification and specimen labelling errors in Irish clinical laboratories. METHODS: A survey was developed by the Clinical Biochemistry Unit, Trinity College Dublin and the Irish External Quality Assessment Scheme (IEQAS), with the intention of gathering key information from each laboratory. Thirty-nine questions were organized into seven subsections covering general information, labelling requirements, information availability, rejection criteria, error monitoring, error reporting and interest in participation in an external quality assessment scheme. The survey was sent electronically to 63 laboratory quality managers at 55 laboratories in Ireland. RESULTS: A total of 39 responses (61% response rate) provided information on 94 separate laboratory departments or disciplines. Laboratories reported varying practices and requirements for labelling specimens and all accepted handwritten preprinted request forms. All (100%) respondents had defined rejection criteria both for specimen labelling and request form completion. Unsurprisingly, the rejection criteria differed between the various laboratory disciplines. Almost all respondents provided information to clinical staff on labelling requirements, but just over half provided training on the same. A large percentage of laboratories (74%) monitored the rate of specimen-labelling errors; however, only 46% had defined target limits for acceptable rates of error. CONCLUSION: The survey observed a wide variation in collection, recording and monitoring of errors but also confirmed significant interest in improving preanalytical monitoring and data collection.

Transoral robotic resection of a retropharyngeal parathyroid adenoma: a case report.

Transoral robotic surgery (TORS) has become an increasingly popular option for early malignancies of the oropharynx. It offers superior visualization and has been proven to have acceptable functional and oncologic outcomes. Additionally, indications in head neck have expanded to manage tumors of the thyroid, neck, parapharyngeal space and salivary glands. A 58-year-old female had an incidental finding on CT imaging of a retropharyngeal mass at the level of the hyoid bone. She was referred to a tertiary medical center for further workup and removal of this mass. Due to the midline position of the mass, favorable access and potentially decreased surgical morbidity, TORS excision of the mass was performed for diagnosis and treatment. Histopathology confirmed this to be a hypercellular parathyroid mass consistent with parathyroid adenoma. We report a relatively unusual location of parathyroid adenoma in an asymptomatic patient with normal parathyroid and calcium levels. TORS proves to be a feasible and safe method for complete surgical excision of retropharyngeal parathyroid adenoma without tumor spillage or violation.

Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin.

Ridinilazole, a novel targeted antibacterial being developed for the treatment of C. difficile infection (CDI) and prevention of recurrence, was shown in a recent Phase 2 study to be superior to vancomycin with regard to the primary efficacy measure, sustained clinical response (SCR), with the superiority being driven primarily by marked reductions in the rates of CDI recurrence within 30 days. Tolerability of ridinilazole was comparable to that of vancomycin. The current nested cohort study compared the effects of ridinilazole and vancomycin on fecal microbiota during and after treatment among participants in the Phase 2 study. Changes in the microbiota were assessed using qPCR and high-throughput sequencing on participants' stools collected at multiple time-points (baseline [Day 1], Day 5, end-of-treatment [EOT; Day 10], Day 25, end-of-study [EOS; Day 40], and at CDI recurrence). qPCR analyses showed profound losses of Bacteroides, C. coccoides, C. leptum, and Prevotella groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in C. leptum group levels at EOT, with levels recovering by Day 25. Vancomycin-treated participants had a significant increase in the Enterobacteriaceae group, with this increase persisting beyond EOT. At EOT, alpha diversity decreased with both antibiotics, though to a significantly lesser extent with ridinilazole (p <0.0001). Beta diversity analysis showed a significantly larger weighted Unifrac distance from baseline-to-EOT with vancomycin. Taxonomically, ridinilazole had a markedly narrower impact, with modest reductions in relative abundance in Firmicutes taxa. Microbiota composition returned to baseline sooner with ridinilazole than with vancomycin. Vancomycin treatment resulted in microbiome-wide changes, with significant reductions in relative abundances of Firmicutes, Bacteroidetes, Actinobacteria, and a profound increase in abundance of Proteobacteria. These findings demonstrate that ridinilazole is significantly less disruptive to microbiota than vancomycin, which may contribute to the reduced CDI recurrence observed in the Phase 2 study.

Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice.

Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1ß concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week-old male A/J mice were fed a low-fat (LF) diet, high-fat (HF) diet or HF+ whole freeze-dried Pd (HF + Pd, 0.04% wt/wt) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane. PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF + Pd mice (0 of 20) (p = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action.