Plasmid Acquisition Alters Vancomycin Susceptibility in Clostridioides difficile.

The increasing incidence of primary and recurring Clostridioides difficile infections (CDI), which evade current treatment strategies, reflects the changing biology of C difficile. Here, we describe a putative plasmid-mediated mechanism potentially driving decreased sensitivity of C difficile to vancomycin treatment. We identified a broad host range transferable plasmid in a C difficile strain associated with lack of adequate response to vancomycin treatment. The transfer of this plasmid to a vancomycin-susceptible C difficile isolate decreased its susceptibility to vancomycin in vitro and resulted in more severe disease in a humanized mouse model. Our findings suggest plasmid acquisition in the gastrointestinal tract to be a possible mechanism underlying vancomycin treatment failure in patients with CDI, but further work is needed to characterize the mechanism by which plasmid genes determine vancomycin susceptibility in C difficile.

Clostridioides difficile Whole-genome Sequencing Differentiates Relapse With the Same Strain From Reinfection With a New Strain.

BACKGROUND: Current approaches in tracking Clostridioides difficile infection (CDI) and individualizing patient management are incompletely defined. METHODS: We recruited 468 subjects with CDI at Mayo Clinic Rochester between May and December 2016 and performed whole-genome sequencing (WGS) on C. difficile isolates from 397. WGS was also performed on isolates from a subset of the subjects at the time of a recurrence of infection. The sequence data were analyzed by determining core genome multilocus sequence type (cgMLST), with isolates grouped by allelic differences and the predicted ribotype. RESULTS: There were no correlations between C. difficile isolates based either on cgMLST or ribotype groupings and CDI outcome. An epidemiologic assessment of hospitalized subjects harboring C. difficile isolates with ≤2 allelic differences, based on standard infection prevention and control assessment, revealed no evidence of person-to-person transmission. Interestingly, community-acquired CDI subjects in 40% of groups with ≤2 allelic differences resided within the same zip code. Among 18 subjects clinically classified as having recurrent CDI, WGS revealed 14 with initial and subsequent isolates differing by ≤2 allelic differences, suggesting a relapse of infection with the same initial strain, and 4 with isolates differing by >50 allelic differences, suggesting reinfection. Among the 5 subjects classified as having a reinfection based on the timing of recurrence, 3 had isolates with ≤2 allelic differences between them, suggesting a relapse, and 2 had isolates differing by >50 allelic differences, suggesting reinfection. CONCLUSIONS: Our findings point to potential transmission of C. difficile in the community. WGS better differentiates relapse from reinfection than do definitions based on the timing of recurrence.

Vulvar Crohn's Disease: Clinical Features and Outcomes.

INTRODUCTION: Vulvar involvement is a rare complication of Crohn's disease (CD). The optimal treatment of vulvar CD is unknown. METHODS: We conducted a 25-year retrospective cohort study of vulvar CD from 3 referral centers. Clinical features and outcomes were studied. RESULTS: Fifty patients were identified. The most common vulvar symptoms were pain (74%), edema (60%), ulcerations (46%), nodules (36%), and abscess (34%). Medical management leading to symptomatic improvement varied, and 5 patients ultimately required surgery. DISCUSSION: Vulvar CD manifests with a broad spectrum of symptoms. Aggressive medical management was frequently effective, although surgery was required in 10% of cases.

Low Risk of Primary Clostridium difficile Infection With Tetracyclines: A Systematic Review and Metaanalysis.

Background: The choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and metaanalysis of studies that assessed the risk of CDI with tetracyclines compared to other antibiotics. Methods: We conducted a systematic search of Medline, Embase, and Web of Science from January 1978 through December 2016 to include studies that assessed the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale. Results: Six studies (4 case control, 2 cohort) with patient recruitment between 1993 and 2012 were included. Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47-0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40-0.75; P < .001). Conclusions: Metaanalyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease CDI associated with antibiotic use.

Coordinated allele-specific histone acetylation at the differentially methylated regions of imprinted genes.

Genomic imprinting is an epigenetic inheritance system characterized by parental allele-specific gene expression. Allele-specific DNA methylation and chromatin composition are two epigenetic modification systems that control imprinted gene expression. To get a general assessment of histone lysine acetylation at imprinted genes we measured allele-specific acetylation of a wide range of lysine residues, H3K4, H3K18, H3K27, H3K36, H3K79, H3K64, H4K5, H4K8, H4K12, H2AK5, H2BK12, H2BK16 and H2BK46 at 11 differentially methylated regions (DMRs) in reciprocal mouse crosses using multiplex chromatin immunoprecipitation SNuPE assays. Histone acetylation marks generally distinguished the methylation-free alleles from methylated alleles at DMRs in mouse embryo fibroblasts and embryos. Acetylated lysines that are typically found at transcription start sites exhibited stronger allelic bias than acetylated histone residues in general. Maternally methylated DMRs, that usually overlap with promoters exhibited higher levels of acetylation and a 10% stronger allele-specific bias than paternally methylated DMRs that reside in intergenic regions. Along the H19/Igf2 imprinted domain, allele-specific acetylation at each lysine residue depended on functional CTCF binding sites in the imprinting control region. Our results suggest that many different histone acetyltransferase and histone deacetylase enzymes must act in concert in setting up and maintaining reciprocal parental allelic histone acetylation at DMRs.

Sequential Prefrontal and Temporoparietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment of Tinnitus With and Without Comorbid Depression: A Case Series and Systematic Review.

Background: Tinnitus distress is related to both the loudness and intrusiveness of the tinnitus percept. Treatment approaches targeting both attentional/limbic and auditory systems may better alleviate tinnitus distress than approaches targeting the auditory system alone. Materials and Methods: Ten subjects with chronic tinnitus received sequential rTMS treatment involving: 1) excitatory stimulation administered to the left dorsolateral prefrontal cortex (DLPFC) or inhibitory stimulation administered to the right DLPFC, followed by 2) inhibitory stimulation administered to primary auditory cortex (Heschel's gyrus or HG). A systematic literature review was performed to evaluate the existing literature on sequential repetitive Transcranial Magnetic Stimulation (rTMS) treatment approaches for tinnitus. Results of the case series are interpreted in the context of tinnitus neurobiology and the extant literature. Results: Subjects experienced a significant decrease (average 21.7%) in symptoms on the Tinnitus Functional Index (TFI). Those with tinnitus alone experienced a greater mean symptom reduction than those with comorbid MDD (27.7 vs. 17.0%, respectively). Adverse effects were transient and minor. Literature review confirmed that sequential approaches had some advantages compared to single site rTMS; in general, the addition of 1 Hz treatment at DLPFC was superior to single site rTMS in the short term (1-12 weeks), while the addition of 20 Hz treatment at DLPFC appeared superior in the long term (90-180 days). Conclusions: Sequential rTMS approaches for the treatment of tinnitus-particularly those administering low-frequency treatment at left DLPFC-merit further investigation.

The dynamics of social support and affective well-being before and during COVID: An experience sampling study.

Based on the dynamic motivational activation (DMA) theoretical framework, this study examines the dynamic, reciprocal relationship between social support and affective well-being in both face-to-face (F2F) and online channels before and during the COVID-19 pandemic. Using experience sampling method, 2002 surveys on F2F and online interactions were collected from 64 participants. Dynamic panel modeling results showed that emotional support was associated with lower emotional discomfort toward F2F and online social interactions. Then, the emotional discomfort toward the F2F interactions drove the subsequent pursuit of emotional support, practical support, and informational support on the online channels. Additionally, findings suggested that individuals were more likely to obtain informational support via F2F communication after experiencing stronger emotional discomfort online during the pandemic.

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Update on Treatment of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is the leading cause of health care-associated infections in the United States. The increasing incidence and recurrence rates of CDI together with its associated morbidity and mortality are great concerns. Newer treatment methods, such as narrow-spectrum antibiotics, monoclonal antibodies, and microbial replacement therapies, are being developed and implemented. We searched PubMed to identify published literature from 2010 to 2018 using the following keywords: Clostridium difficile, treatment, and therapy. Cited references were also used to identify relevant literature. This review focuses on the current standard of therapy and emerging therapies for CDI and summarizes the updated guidelines on treatment of CDI.

Developing an Open Access, Competency-Based Global Oral Health Curriculum: A Global Health Starter Kit.

Dental education has seen increases in global health and international educational experiences in many dental schools' curricula. In response, the Consortium of Universities for Global Health's Global Oral Health Interest Group aims to develop readily available, open access resources for competency-based global oral health teaching and learning. The aim of this study was to develop and evaluate a Global Health Starter Kit (GHSK), an interdisciplinary, competency-based, open access curriculum for dental faculty members who wish to teach global oral health in their courses. Phase I (2012-17) evaluated longitudinal outcomes from two Harvard School of Dental Medicine pilot global health courses with 32 advanced and 34 predoctoral dental students. In Phase II (2018), the Phase I outcomes informed development, implementation, and evaluation of the open access GHSK (45 enrollees) written by an interdisciplinary, international team of 13 content experts and consisting of five modules: Global Trends, Global Goals, Back to Basics: Primary Care, Social Determinants and Risks, and Ethics and Sustainability. In Phase III (summer and fall 2018), five additional pilot institutions (two U.S. dental schools, one U.S. dental hygiene program, and two dental schools in low- and middle-income countries) participated in an early adoption of the GHSK curriculum. The increase in perceived knowledge scores of students enrolled in the pilot global health courses was similar to those enrolled in the GHSK, suggesting the kit educated students as well or better in nearly all categories than prior course materials. This study found the GHSK led to improvements in learning in the short term and may also contribute to long-term career planning and decision making by providing competency-based global health education.

Hyperammonemic encephalopathy in a patient with fibrolamellar hepatocellular carcinoma: case report and literature review.

Fibrolamellar hepatocellular carcinoma (fHCC) is a rare primary liver cancer that affects young adults with no prior liver disease. fHCC-associated hyperammonemic encephalopathy (HAE) is an uncommon and life-threatening complication. Hyperammonemia has been reported in both typical and fHCC as a result of intrahepatic shunting, side effect from immunotherapy or chemotherapy, or as a paraneoplastic phenomenon. We present a case of a 32-year-old woman with recurrent metastatic fHCC who developed HAE in the setting of steroid administration. Her hyperammonemia was exacerbated by steroid-induced protein catabolism. She was treated with ammonia scavenging medications, a low protein diet, and was placed on chronic ammonia scavenger therapy while undergoing chemotherapy. In this case report, we discuss the proposed mechanisms of HAE, and we review the literature regarding clinical presentation and treatment.

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.

Therapeutic Implications of the Genetic Landscape of Head and Neck Cancer.

Large-scale sequencing studies of head and neck squamous cell carcinoma (HNSCC) have elucidated the genetic changes that characterize HNSCC. These findings have supported the development of therapeutic strategies that target key components of aberrant signaling pathways and immune dysregulation. Cumulative evidence suggests that these agents in combination with radiotherapy may have synergistic effects. This review highlights the predictive biomarkers that have been identified from HNSCC genomic studies and implications on the development of molecular-targeting agents that may effectively treat patients with HNSCC, especially when used in combination with radiation.

Screening for Clostridium difficile colonization on admission to a hematopoietic stem cell transplant unit may reduce hospital-acquired C difficile infection.

Clostridium difficile infection rates are higher in patients undergoing hematopoietic stem cell transplants. In our study, patients undergoing hematopoietic stem cell transplants or chemotherapy were screened for C difficile colonization at admission and placed on contact precautions if they were positive. Patient's colonized with C difficile contribute to the overall burden of C difficile infection in hospitals.

Association between atopic dermatitis and squamous cell carcinoma: a case-control study.

BACKGROUND: Conflicting data have been published on whether an association exists between atopic dermatitis (AD) and nonmelanoma skin cancer. This study aimed to determine whether individuals with AD had an increased risk of squamous cell carcinoma (SCC) development. METHODS: We conducted a retrospective, case-control study of patients residing in Olmsted County, Minnesota. Cases were selected from patients seen at Mayo Clinic (Rochester, Minnesota) who had an initial SCC diagnosis (either invasive SCC or SCC in situ) from January 1, 1996, through December 23, 2010. Age- and sex-matched controls were selected from patients seen at Mayo Clinic with no history of SCC before the case event date. RESULTS: Three hundred ninety-nine individuals with a documented history of SCC were identified and matched with 780 controls who did not have a history of SCC. After adjusting for race, smoking history, ionizing radiation exposure, corticosteroid and cyclosporine use, and non-SCC skin cancers, the odds ratio for SCC development between patients with history of AD versus patients without history of AD was 1.75 (95% CI, 1.05-2.93). CONCLUSIONS: Our findings support an increased risk of SCC development in the setting of AD.

Role of imaging in the diagnosis of occult hernias.

IMPORTANCE: Occult hernias are symptomatic but not palpable on physical examination. This is more commonly seen with inguinal hernias. Early diagnosis and treatment of occult hernias are essential in relieving symptoms and improving patients' quality of life. OBJECTIVE: To determine the effectiveness of imaging-ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI)--in the diagnosis of occult inguinal hernia. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical records review of surgical patients with groin and pelvic pain, 2008-2013, was conducted in a single-surgeon hernia specialty practice. Thirty-six patients met the following inclusion criteria: (1) examination findings suggestive of but not necessarily diagnostic for inguinal hernia; (2) imaging of the groin and/or pelvis with US, CT, and MRI; and (3) an operation to address the groin or pelvic pain. Fifty-nine groins were included. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and predictive values of US, CT, and MRI for detection of occult inguinal hernia. RESULTS: The number, sensitivity, specificity, positive predictive value, and negative predictive value of each modality were, respectively: US (9, 0.33, 0, 1.00, and 0), CT (39, 0.54, 0.25, 0.86, and 0.06), and MRI (34, 0.91, 0.92, 0.95, and 0.85). Among multiply imaged groins in which CT examination missed a diagnosis of hernia, MRI correctly detected an occult hernia in 10 of 11 cases (91%). CONCLUSIONS AND RELEVANCE: Ultrasonography and CT cannot reliably exclude occult groin abnormalities. Patients with clinical suspicion of inguinal hernia should undergo MRI as the definitive radiologic examination.