Citations

Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

Abstract Objective: Hypertensive disorders of pregnancy and menopausal symptoms, specifically vasomotor symptoms, have both been associated with cardiovascular disease risk in women. However, data are sparse on the association between these two female-specific cardiovascular risk factors. This study was conducted to investigate the association between a history of a hypertensive disorder of pregnancy and menopausal symptoms. Methods: This was a cross-sectional study of women aged 40 to 65 years seen for specialty consultation in women's health clinics at Mayo Clinic Rochester, MN and Scottsdale, AZ, between May, 2015 and September, 2019. A self-reported history of hypertensive disorders of pregnancy served as the independent variable, and menopause symptoms as assessed by the Menopause Rating Scale were the primary outcome measure. Results: Of 2,684 women included in the analysis, 180 had a self-reported history of a hypertensive disorder of pregnancy. The total menopausal symptom scores as well as somatic and psychological domain scores were higher in women with a history of a hypertensive disorder of pregnancy compared to women without a history of a hypertensive disorder of pregnancy or to women without a pregnancy. On multivariable analysis, women with a hypertensive disorder of pregnancy using hormone therapy had significantly higher total menopause symptom scores than women with no such history. Conclusions: In this large cross-sectional study, a history of hypertensive disorders of pregnancy was associated with more bothersome menopausal symptoms. Additional study is needed to determine the strength of this association, underlying mechanisms of the association, and clinical implications for cardiovascular risk prediction in women.

Background: Management of patients with advanced medullary thyroid cancer (MTC) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib have been approved for the treatment of progressive MTC based on prolonged progression-free survival (PFS) in phase 3 clinical trials. Patients and Methods: To evaluate clinical characteristics, treatment regimens, efficacy, and treatment emergent adverse events (TEAEs) of vandetanib and cabozantinib in MTC patients outside clinical trials at four German tertiary care centers. Forty-eight patients diagnosed between 1990 and 2018 were included. PFS and overall survival (OS) probabilities were estimated using the Kaplan–Meier method and compared by log-rank test. Results: The median age at diagnosis was 46 years (15–80 years); a germ line RET (rearranged during transfection) mutation was known in 6 (13%) patients. Thirty-two (67%) patients showed progressive disease before TKI initiation. Forty-seven (98%) patients were treated with vandetanib and 23 (48%) patients with cabozantinib. Vandetanib was first-line treatment in 41 (85%) patients and cabozantinib in 7 (15%) patients. Partial response was the best response in 12 (26%) patients treated with vandetanib and in 5 (22%) patients treated with cabozantinib. Sixteen (34%) patients treated with vandetanib and 3 (13%) patients treated with cabozantinib had stable disease ≥24 weeks. The median PFS for vandetanib and cabozantinib was 17 months [95% confidence interval, CI, 9.3–24.6 months] and 4 months [CI 3.1–4.9 months], respectively. The 6- and 12-month survival rates were 98% and 86% for vandetanib and 78% and 70% for cabozantinib, respectively. The median OS for vandetanib and cabozantinib was 53 months [CI 43.7–62.3 months] and 24 months [CI 5.9–42.1 months], respectively. In vandetanib-treated patients, the PFS and OS were significantly longer in patients aged ≤60 years at TKI initiation and in patients with ≥5 TEAEs. Additionally, the PFS was longer in the absence of bone metastases. In cabozantinib-treated patients, the PFS was significantly longer in patients experiencing TEAEs and in patients aged ≤60 years, and the OS was significantly longer in patients who had TEAEs and in patients with ≥5 TEAEs. Conclusions: Vandetanib and cabozantinib are effective treatment options in the majority of MTC patients. We hypothesize that the poorer prognosis of cabozantinib-treated patients in our retrospective analysis is most likely due to its use as second-line treatment after treatment failure on vandetanib. However, different degrees of efficacy of the two drugs are possible.

AbstractNeuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Abstract Background There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD. Methods Duodenal mucosal ion transport (basal and acetylcholine‐ and glucose‐evoked changes in short‐circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls. Results Basal Isc (FD: 88.2 [52.6] μA/cm 2 vs healthy: 20.3 [50.2] μA/cm 2 ; P ≤ .0001), acetylcholine‐evoked Isc (FD: Emax 50.4 [35.8] μA/cm 2 vs healthy: 16.6 [15] μA/cm 2 ; P ≤ .001), and glucose‐evoked Isc responses (FD: E max 69.8 [42.1] μA/cm 2 vs healthy: 40.3 [24.6] μA/cm 2 ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4 , which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa‐miR‐590‐3p, hsa‐miR‐32‐5p) that target genes associated with ionic transport were upregulated in FD. Conclusions Compared to controls, FD patients had greater baseline and agonist‐evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.

Abstract Background Obesity and female sexual dysfunction (FSD) are prevalent conditions, and both are associated with significant adverse effects on health and well-being. Aim To investigate the association between body mass index and FSD, as well as potential moderators. Methods This cross-sectional study was performed by analyzing medical records of 6,688 women seeking consultation for menopause-related or sexual health–related concerns at women’s health clinics at Mayo Clinic Rochester, MN, and Scottsdale, AZ, between May 1, 2015, and September 15, 2019. Outcomes Female sexual function was assessed by the Female Sexual Function Index, and sexual distress was assessed by the Female Sexual Distress Scale-Revised. Results Being overweight or obese was associated with a lack of sexual activity. Among sexually active women, those who were overweight or obese had lower Female Sexual Function Index total scores and sexual function domain scores (indicating worse sexual function), including sexual arousal, lubrication, satisfaction, orgasm, and pain, and higher levels of sexual distress than those with normal weight. However, on multivariable analysis, these associations were found to be mediated by other factors, including age, level of education, reproductive stage, medication use, and mood disturbances, which are known to impact body weight and sexual function in women. Clinical Implications Overweight and obesity were associated with sexual inactivity and greater odds of having FSD, which should prompt proactive assessment of sexual function. Strengths and Limitations The strengths of this study include the large cohort size and assessment of sexual problems in addition to sexual distress, a key component of the definition of sexual dysfunction. This study also took into account multiple potential moderating factors. Limitations include the cross-sectional design, which precludes determination of causality as well as lack of diversity in the cohort, potentially limiting generalizability of results. In addition, sexual function was not assessed in women reporting no recent sexual activity, which may confound results. Conclusion Overweight/obesity and FSD are highly prevalent conditions, which appear to be indirectly associated. These results highlight the need to identify and address FSD in all overweight and obese women, with particular attention to potential contributing factors.

AbstractIntroductionAs hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain.MethodsA total of 1086 dementia‐free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population‐based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016–2017) and magnetic resonance imaging of the brain (2011–2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts.ResultsHearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus.ConclusionOur results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes.

Date Presented 03/26/20 In adults with first carpometacarpal degenerative joint disease, does a dynamic stabilization home exercise program (HEP) decrease pain and increase function more than a traditional HEP? Research is needed to assess if this approach will lead to greater function and less pain than the currently accepted approach. It is important for OTs to have a holistic approach that includes traditional joint protection, orthosis use, and self-management of HEPs. Primary Author and Speaker: Cindy Ivy Additional Authors and Speakers: Kaylee Martino, Sara Murphy, Celine De Jesus, Stephanie Kannas, Kimberly McVeigh, Allison Nickolaou