Connectivity of the Superficial Muscles of the Human Perineum: A Diffusion Tensor Imaging-Based Global Tractography Study.

Despite the importance of pelvic floor muscles, significant controversy still exists about the true structural details of these muscles. We provide an objective analysis of the architecture and orientation of the superficial muscles of the perineum using a novel approach. Magnetic Resonance Diffusion Tensor Images (MR-DTI) were acquired in 10 healthy asymptomatic nulliparous women, and 4 healthy males. Global tractography was then used to generate the architecture of the muscles. Micro-CT imaging of a male cadaver was performed for validation of the fiber tracking results. Results show that muscles fibers of the external anal sphincter, from the right and left side, cross midline in the region of the perineal body to continue as transverse perinea and bulbospongiosus muscles of the opposite side. The morphology of the external anal sphincter resembles that of the number '8' or a "purse string". The crossing of muscle fascicles in the perineal body was supported by micro-CT imaging in the male subject. The superficial muscles of the perineum, and external anal sphincter are frequently damaged during child birth related injuries to the pelvic floor; we propose the use of MR-DTI based global tractography as a non-invasive imaging technique to assess damage to these muscles

Teaching health advocacy to medical students: a comparison study.

CONTEXT: Many encourage service learning and health advocacy training in medical student education, but related evaluation is limited. OBJECTIVES: To assess (1) impact of a required community health advocacy training for medical students on student attitudes, knowledge, and skills; (2) student characteristics associated with higher advocacy knowledge and skills; and (3) perspectives of community-based organizations (CBOs). DESIGN: Cross-sectional surveys. SETTING: University of Miami Miller School of Medicine (UMMSM) Regional Medical Campus and main campus. PARTICIPANTS: Medical students at both UMMSM campuses. INTERVENTION: Required community health advocacy training for first- and second-year students including classroom experiences and hands-on project in partnership with a CBO. MAIN OUTCOME MEASURES: Student characteristics, health advocacy-related attitudes, self-reported and objective knowledge, and skills. Scores were compared between campuses, with multivariable modeling adjusting for individual student characteristics. Community-based organization perspectives were assessed via separate surveys. RESULTS: Ninety-eight (77%) regional campus students (intervention group) and 139 (30%) main campus students (comparison group) completed surveys. Versus the comparison group, the intervention group reported greater: mean knowledge of community health needs: 34.6 versus 31.1 (range: 11-44, P \u3c .01), knowledge about CBOs: 3.0 versus 2.7 (range 1-4, P \u3c .01) and knowledge of community resources: 5.4 versus 2.3 (range, 0-11, P \u3c .01), and mean skill scores: 12.7 versus 10.5 (score range: 4-16, P \u3c .01), following the intervention. Using adjusted analysis across both groups, female gender was associated with higher attitudes score. High level of previous community involvement was associated with higher attitude and skill scores. Higher self-reported educational debt was associated with higher skill scores. Community-based organization perspectives included high satisfaction and a desire to influence the training of future physicians. CONCLUSIONS: Medical student advocacy training in partnership with community-based organizations could be beneficial in improving student advocacy knowledge and skills in addressing community health issues and in developing sustainable community partnerships

Delayed presentation of symptomatic breast cancers in Hong Kong: Experience in a public cancer centre

Objective Delayed presentation is an important obstacle to improving cancer treatment outcomes. We aimed to study the magnitude of this problem in Hong Kong and the factors associated with delayed presentation of patients with symptomatic breast cancers. Design Retrospective study using self-administered questionnaires. Setting Clinical Oncology Department in a regional public hospital in Hong Kong. Patients A total of 158 Chinese women with breast cancer referred to our hospital between October 2006 and December 2007 consented to participate in this study. Among these, 59 (37%) patients were referred after having surgery in private sector. Results The mean total delay (from first symptom to treatment) was 22 weeks. The mean patient delay (from first symptom to first consultation) was 13 weeks, constituting the largest component (60%) of the total delay. After symptom onset, the delay exceeded 12 weeks for consulting a doctor in 29%, and for receipt of treatment in 52% of them. Low family income (<HK$5000 per month; P<0.001) and surgery in public hospitals (P=0.013) were both independent predictors of patient delay. Surgery in public hospitals (P=0.006) and low family income (P=0.005) were the only predictors of doctor/system delay and total delay, respectively. Conclusions Delayed presentation and treatment of symptomatic breast cancer remains an important issue in Hong Kong. Apart from socio-economic factors, limited access to public medical care was likely an important contributing factor in delays related to patients as well as to doctor/system.published_or_final_versio

Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence

The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the stringent response enzyme RelMtb was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved relMtb-deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of relMtb increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of RelMtb and showed that the lead compound X9 was able to directly kill nutrient-starved M. tuberculosis and enhanced the killing activity of isoniazid. Inhibition of RelMtb is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.This work was supported by R01AI083125, R21AI122922, and R21AI114507A to P.C.

The acceptability of PEGASUS: An intervention to facilitate shared decision-making with women contemplating breast reconstruction

© 2015 The Author(s). Published by Taylor & Francis. Good practice guidelines recommend that women who undergo mastectomy are offered reconstructive surgery. However, many who choose this option report a degree of decisional regret and dissatisfaction because their pre-surgical expectations were not met. This paper reports an acceptability study of a new intervention (PEGASUS) that aims to support shared decision-making by eliciting womens pre-surgical expectations and setting patient-centred goals. Eighteen women contemplating breast reconstruction completed the PEGASUS intervention. Semi-structured interviews were conducted with 12 women and 3 health professionals to explore their experiences of using PEGASUS. Interview transcripts were subjected to a thematic analysis, and a content analysis was conducted on 79 goals that the 18 women identified. Feedback was extremely positive - women found that completing PEGASUS alongside a discussion with a specially trained health professional helped them prepare for the surgical consultation and increased their trust in their surgeon. Staff reported that PEGASUS facilitated patient-centred discussions and informed the decisions made about potential surgery. This preliminary study suggests that this novel intervention is acceptable to patients and health professionals alike. Further work is needed to evaluate its efficacy and then its effectiveness with a larger sample of women, and its potential use with other patient groups

Acute Drug Treatment in the Early C. elegans Embryo

Genetic and genome-wide RNAi approaches available in C. elegans, combined with tools for visualizing subcellular events with high-resolution, have led to increasing adoption of the early C. elegans embryo as a model for mechanistic and functional genomic analysis of cellular processes. However, a limitation of this system has been the impermeability of the embryo eggshell, which has prevented the routine use of small molecule inhibitors. Here, we present a method to permeabilize and immobilize embryos for acute inhibitor treatment in conjunction with live imaging. To identify a means to permeabilize the eggshell, we used a dye uptake assay to screen a set of 310 candidate genes defined by a combination of bioinformatic criteria. This screen identified 20 genes whose inhibition resulted in >75% eggshell permeability, and 3 that permeabilized embryos with minimal deleterious effects on embryo production and early embryonic development. To mount permeabilized embryos for acute drug addition in conjunction with live imaging, we combined optimized inhibition of one of these genes with the use of a microfabricated chamber that we designed. We demonstrate that these two developments enable the temporally controlled introduction of inhibitors for mechanistic studies. This method should also open new avenues of investigation by allowing profiling and specificity-testing of inhibitors through comparison with genome-wide phenotypic datasets

Structural basis for CRISPR RNA-guided DNA recognition by Cascade

The CRISPR (clustered regularly interspaced short palindromic repeats) immune system in prokaryotes uses small guide RNAs to neutralize invading viruses and plasmids. In Escherichia coli, immunity depends on a ribonucleoprotein complex called Cascade. Here we present the composition and low-resolution structure of Cascade and show how it recognizes double-stranded DNA (dsDNA) targets in a sequence-specific manner. Cascade is a 405-kDa complex comprising five functionally essential CRISPR-associated (Cas) proteins (CasA1B2C6D1E1) and a 61-nucleotide CRISPR RNA (crRNA) with 5′-hydroxyl and 2′,3′-cyclic phosphate termini. The crRNA guides Cascade to dsDNA target sequences by forming base pairs with the complementary DNA strand while displacing the noncomplementary strand to form an R-loop. Cascade recognizes target DNA without consuming ATP, which suggests that continuous invader DNA surveillance takes place without energy investment. The structure of Cascade shows an unusual seahorse shape that undergoes conformational changes when it binds target DNA.

Ancient DNA Analysis of the Oldest Canid Species from the Siberian Arctic and Genetic Contribution to the Domestic Dog

Modern Arctic Siberia provides a wealth of resources for archaeological, geological, and paleontological research to investigate the population dynamics of faunal communities from the Pleistocene, particularly as the faunal material coming from permafrost has proven suitable for genetic studies. In order to examine the history of the Canid species in the Siberian Arctic, we carried out genetic analysis of fourteen canid remains from various sites, including the well-documented Upper Paleolithic Yana RHS and Early Holocene Zhokhov Island sites. Estimated age of samples range from as recent as 1,700 years before present (YBP) to at least 360,000 YBP for the remains of the extinct wolf, Canis cf. variabilis. In order to examine the genetic affinities of ancient Siberian canids species to the domestic dog and modern wolves, we obtained mitochondrial DNA control region sequences and compared them to published ancient and modern canid sequences. The older canid specimens illustrate affinities with pre-domestic dog/wolf lineages while others appear in the major phylogenetic clades of domestic dogs. Our results suggest a European origin of domestic dog may not be conclusive and illustrates an emerging complexity of genetic contribution of regional wolf breeds to the modern Canis gene pool

Enabling Space Exploration Medical System Development Using a Tool Ecosystem

The NASA Human Research Program's (HRP) Exploration Medical Capability (ExMC) Element is utilizing a Model Based Systems Engineering (MBSE) approach to enhance the development of systems engineering products that will be used to advance medical system designs for exploration missions beyond Low Earth Orbit. In support of future missions, the team is capturing content such as system behaviors, functional decompositions, architecture, system requirements and interfaces, and recommendations for clinical capabilities and resources in Systems Modeling Language (SysML) models. As these products mature, SysML models provide a way for ExMC to capture relationships among the various products, which includes supporting more integrated and multi-faceted views of future medical systems. In addition to using SysML models, HRP and ExMC are developing supplementary tools to support two key functions: 1) prioritizing current and future research activities for exploration missions in an objective manner; and 2) enabling risk-informed and evidence-based trade space analysis for future space vehicles, missions, and systems. This paper will discuss the long-term HRP and ExMC vision for the larger ecosystem of tools, which include dynamic Probabilistic Risk Assessment (PRA) capabilities, additional SysML models, a database of system component options, and data visualizations. It also includes a review of an initial Pilot Project focused on enabling medical system trade studies utilizing data that is coordinated across tools for consistent outputs (e.g., mission risk metrics that are associated with medical system mass values and medical conditions addressed). This first Pilot Project demonstrated successful operating procedures and integration across tools. Finally, the paper will also cover a second Pilot Project that utilizes tool enhancements such as medical system optimization capabilities, post-processing, and visualization of generated data for subject matter expert review, and increased integration amongst the tools themselves

Association Between Acute Neuropsychiatric Events and Helicobacter pylori Therapy Containing Clarithromycin.

IMPORTANCE: There is a concern that Helicobacter pylori therapy containing clarithromycin might be associated with acute neuropsychiatric events. OBJECTIVE: To examine the association between H pylori therapy containing clarithromycin and acute neuropsychiatric events. DESIGN, SETTING, AND PARTICIPANTS: A self-controlled case series study was conducted using the Clinical Data Analysis and Reporting System database in Hong Kong to explore any association. The exposure of interest was H pylori therapy containing clarithromycin in the outpatient setting. Study patients, 18 years or older at cohort entry, must have had both exposure to H pylori therapy containing clarithromycin and their first recorded neuropsychiatric events between January 1, 2003, and December 31, 2012. A post hoc nested case-control analysis was also performed in patients receiving H pylori therapy containing clarithromycin. MAIN OUTCOMES AND MEASURES: The primary outcome was composite neuropsychiatric events, while secondary outcomes were psychotic events and cognitive impairment. Risk periods in the self-controlled case series analysis were defined as 14-day preexposure period, current use (days 1-14 since prescription start date) and recent use (days 15-30). Age-adjusted incidence rate ratios (IRR) were estimated using the conditional Poisson regression. RESULTS: Of 66 559 patients who had at least 1 outpatient prescription of H pylori therapy containing clarithromycin. Their mean (SD) age at cohort entry was 50.8 (14.8 years); their mean age at first exposure was 55.4 (14.8) years, and 30 910 were male (46.4%). A total of 1824 patients had their first recorded composite neuropsychiatric events during the study period. An increased IRR of 4.12 (35 composite neuropsychiatric events during 72 person-years; 95% CI, 2.94-5.76) during current use was observed but not in recent use (9 events during 82 person-years; IRR, 0.95; 95% CI, 0.49-1.83) and 14-day preexposure period (14 events during 72 person-years; IRR, 1.63; 95% CI, 0.96-2.77) vs baseline (1766 events during 16 665 person-years). Similarly, both the risk of psychotic events and cognitive impairment increased during current use vs baseline, although this subsequently returned to baseline incidence levels during recent use. The crude absolute risks of composite neuropsychiatric events, psychotic events, and cognitive impairment during current use were 0.45, 0.12, and 0.12 per 1000 prescriptions, respectively. The nested case-control analysis also gave similar results to that of the self-controlled case series analysis. CONCLUSIONS AND RELEVANCE: This study shows evidence of a short-term increased risk of neuropsychiatric events associated with H pylori therapy containing clarithromycin