A one-stop perineal clinic: our eleven-year experience.

INTRODUCTION AND HYPOTHESIS: The perineal clinic is a dedicated setting offering assessment for various childbirth-related presentations including obstetric anal sphincter injuries (OASIs), perineal wound complications, pelvic floor dysfunction and other conditions such as female genital mutilation(FGM). We describe the clinical presentation and outcomes of women from a tertiary perineal clinic based on data collected over an 11-year period. METHODS: This is a retrospective observational study. A one-stop outpatient service was offered to all women who sustained OASIs (postnatally and antenatally in a subsequent pregnancy), perineal complications (within 16 weeks postpartum), FGM and/or peripartum symptoms of urinary/anal incontinence or prolapse. Assessment included history with validated questionnaires, examination and anal manometry and endoanal ultrasound when appropriate. Outcomes were compared among different grades of OASIs. Management of each type of presentation was reported with outcomes. RESULTS: There were 3254 first attendance episodes between 2006 and 2016. The majority (58.1%) were for OASIs, followed by perineal wound complications. Compared to the lower grades, the higher grades of OASI were associated with poorer outcomes in terms of symptoms, investigations and complications. Women with OASIs had unrelated symptoms such as urinary incontinence, perineal pain and wound infections that needed further intervention. A high proportion(42%) of wound complications required further specialist management. CONCLUSION: We describe a dedicated, one-stop perineal clinic model for antenatal and postnatal women for management of perineal and pelvic floor disorders. This comprehensive and novel data will enable clinicians to better counsel women regarding of outcomes after OASI and focus training to minimize risks of morbidities

Faecal pharmacokinetics of orally administered vancomycin in patients with suspected Clostridium difficile infection

<p>Abstract</p> <p>Background</p> <p>Oral vancomycin (125 mg qid) is recommended as treatment of severe <it>Clostridium difficile </it>infection (CDI). Higher doses (250 or 500 mg qid) are sometimes recommended for patients with very severe CDI, without supporting clinical evidence. We wished to determine to what extent faecal levels of vancomycin vary according to diarrhoea severity and dosage, and whether it is rational to administer high-dose vancomycin to selected patients.</p> <p>Methods</p> <p>We recruited hospitalized adults suspected to have CDI for whom oral vancomycin (125, 250 or 500 mg qid) had been initiated. Faeces were collected up to 3 times/day and levels were measured with the AxSYM fluorescence polarization immunoassay.</p> <p>Results</p> <p>Fifteen patients (9 with confirmed CDI) were treated with oral vancomycin. Patients with ≥4 stools daily presented lower faecal vancomycin levels than those with a lower frequency. Higher doses of oral vancomycin (250 mg or 500 mg qid) led to consistently higher faecal levels (> 2000 mg/L), which were 3 orders of magnitude higher than the MIC₉₀of vancomycin against <it>C. difficile</it>. One patient receiving 125 mg qid had levels below 50 mg/L during the first day of treatment.</p> <p>Conclusions</p> <p>Faecal levels of vancomycin are proportional to the dosage administered and, even in patients with increased stool frequency, much higher than the MIC₉₀. Patients given the standard 125 mg qid dosage might have low faecal levels during the first day of treatment. A loading dose of 250 mg or 500 mg qid during the first 24-48 hours followed by the standard dosage should be evaluated in larger studies, since it might be less disruptive to the colonic flora and save unnecessary costs.</p

A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans

<p>Abstract</p> <p>Background</p> <p>A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (<it>INSIG2</it>) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.</p> <p>Methods</p> <p>We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise <it>r</it>^{<it>2 </it>}of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.</p> <p>Results</p> <p>We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.</p> <p>Conclusion</p> <p>Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of <it>INSIG2 </it>in obesity related traits as we found significant association of another tagSNP in <it>INSIG2 </it>with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.</p

Aptamer-based field-effect biosensor for tenofovir detection

During medical treatment it is critical to maintain the circulatory concentration of drugs within their therapeutic range. A novel biosensor is presented in this work to address the lack of a reliable point-of-care drug monitoring system in the market. The biosensor incorporates high selectivity and sensitivity by integrating aptamers as the recognition element and field-effect transistors as the signal transducer. The drug tenofovir was used as a model small molecule. The biointerface of the sensor is a binary self-assembled monolayer of specific thiolated aptamer and 6-mercapto-1-hexanol (MCH), whose ratio was optimized by electrochemical impedance spectroscopy measurements to enhance the sensitivity towards the specific target. Surface plasmon resonance, performed under different buffer conditions, shows optimum specific and little non-specific binding in phosphate buffered saline. The dose-response behavior of the field-effect biosensor presents a linear range between 1 nM and 100 nM of tenofovir and a limit of detection of 1.2 nM. Two non-specific drugs and one non-specific aptamer, tested as stringent control candidates, caused negligible responses. The applications were successfully extended to the detection of the drug in human serum. As demonstrated by impedance measurements, the aptamer-based sensors can be used for real-time drug monitoring

A Meta-Analysis of Probiotic Efficacy for Gastrointestinal Diseases

Background: Meta-analyses on the effects of probiotics on specific gastrointestinal diseases have generally shown positive effects on disease prevention and treatment; however, the relative efficacy of probiotic use for treatment and prevention across different gastrointestinal diseases, with differing etiology and mechanisms of action, has not been addressed. Methods/Principal Findings: We included randomized controlled trials in humans that used a specified probiotic in the treatment or prevention of Pouchitis, Infectious diarrhea, Irritable Bowel Syndrome, Helicobacter pylori, Clostridium difficile Disease, Antibiotic Associated Diarrhea, Traveler’s Diarrhea, or Necrotizing Enterocolitis. Random effects models were used to evaluate efficacy as pooled relative risks across the eight diseases as well as across probiotic species, single vs. multiple species, patient ages, dosages, and length of treatment. Probiotics had a positive significant effect across all eight gastrointestinal diseases with a relative risk of 0.58 (95 % (CI) 0.51–0.65). Six of the eight diseases: Pouchitis, Infectious diarrhea, Irritable Bowel Syndrome, Helicobacter pylori, Clostridium difficile Disease, and Antibiotic Associated Diarrhea, showed positive significant effects. Traveler’s Diarrhea and Necrotizing Enterocolitis did not show significant effects of probiotcs. Of the 11 species and species mixtures, all showed positive significant effects except for Lactobacillus acidophilus, Lactobacillus plantarum, and Bifidobacterium infantis. Across all diseases and probiotic species, positive significant effects of probiotics were observed for all age groups, single vs. multiple species, and treatment lengths

Fluorescence in situ hybridisation analysis of chromosomal aberrations in gastric tissue: the potential involvement of Helicobacter pylori

In this series of experiments, a novel protocol was developed whereby gastric cells were collected using endoscopic cytology brush techniques, and prepared, such that interphase fluorescence in situ hybridization (FISH) could be performed. In total, 80 distinct histological samples from 37 patients were studied using four chromosome probes (over 32 000 cells analysed). Studies have previously identified abnormalities of these four chromosomes in upper GI tumours. Using premalignant tissues, we aimed to determine how early in Correa's pathway to gastric cancer these chromosome abnormalities occurred. Aneuploidy of chromosomes 4, 8, 20 and 17(p53) was detected in histologically normal gastric mucosa, as well as in gastritis, intestinal metaplasia, dysplasia and cancer samples. The levels of aneuploidy increased as disease severity increased. Amplification of chromosome 4 and chromosome 20, and deletion of chromosome 17(p53) were the more common findings. Hence, a role for these abnormalities may exist in the initiation of, and the progression to, gastric cancer. Helicobactor pylori infection was determined in premalignant tissue using histological analysis and PCR technology. Detection rates were comparable. PCR was used to subtype H. pylori for CagA status. The amplification of chromosome 4 in gastric tissue was significantly more prevalent in H. pylori-positive patients (n=7) compared to H. pylori-negative patients (n=11), possibly reflecting a role for chromosome 4 amplification in H. pylori-induced gastric cancer. The more virulent CagA strain of H. pylori was associated with increased disease pathology and chromosomal abnormalities, although numbers were small (CagA+ n=3, CagA− n=4). Finally, in vitro work demonstrated that the aneuploidy induced in a human cell line after exposure to the reactive oxygen species (ROS) hydrogen peroxide was similar to that already shown in the gastric cancer pathway, and may further strengthen the hypothesis that H. pylori causes gastric cancer progression via an ROS-mediated mechanism

TESS hunt for young and maturing exoplanets (THYME). III. A two-planet system in the 400 Myr Ursa major group

A.W.M. was supported through NASA's Astrophysics Data Analysis Program (80NSSC19K0583). M.L.W. was supported by a grant through NASA's K2 GO program (80NSSC19K0097). This material is based on work supported by the National Science Foundation Graduate Research Fellowship Program under grant No. DGE-1650116 to P.C.T. A.V.'s work was performed under contract with the California Institute of Technology/Jet Propulsion Laboratory funded by NASA through the Sagan Fellowship Program executed by the NASA Exoplanet Science Institute. D.D. acknowledges support from NASA through Caltech/JPL grant RSA-1006130 and through the TESS Guest Investigator Program grant 80NSSC19K1727.Exoplanets can evolve significantly between birth and maturity, as their atmospheres, orbits, and structures are shaped by their environment. Young planets (<1 Gyr) offer an opportunity to probe the critical early stages of this evolution, where planets evolve the fastest. However, most of the known young planets orbit prohibitively faint stars. We present the discovery of two planets transiting HD 63433 (TOI 1726, TIC 130181866), a young Sun-like (M∗=0.99±0.03) star. Through kinematics, lithium abundance, and rotation, we confirm that HD 63433 is a member of the Ursa Major moving group (τ=414±23 Myr). Based on the TESS light curve and updated stellar parameters, we estimate the planet radii are 2.15±0.10R⊕ and 2.67±0.12R⊕, the orbital periods are 7.11 and 20.55 days, and the orbital eccentricities are lower than about 0.2. Using HARPS-N velocities, we measure the Rossiter-McLaughlin signal of the inner planet, demonstrating that the orbit is prograde. Since the host star is bright (V=6.9), both planets are amenable to transmission spectroscopy, radial velocity measurements of their masses, and more precise determination of the stellar obliquity. This system is therefore poised to play an important role in our understanding of planetary system evolution in the first billion years after formation.PostprintPeer reviewe

A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease. To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen. These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells

Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines

This article discusses the definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are difficult. Variations in treatment and risk factors influencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria