A dynamically young and perturbed Milky Way disk.

The evolution of the Milky Way disk, which contains most of the stars in the Galaxy, is affected by several phenomena. For example, the bar and the spiral arms of the Milky Way induce radial migration of stars1 and can trap or scatter stars close to orbital resonances2. External perturbations from satellite galaxies can also have a role, causing dynamical heating of the Galaxy3, ring-like structures in the disk4 and correlations between different components of the stellar velocity5. These perturbations can also cause 'phase wrapping' signatures in the disk6-9, such as arched velocity structures in the motions of stars in the Galactic plane. Some manifestations of these dynamical processes have already been detected, including kinematic substructure in samples of nearby stars10-12, density asymmetries and velocities across the Galactic disk that differ from the axisymmetric and equilibrium expectations13, especially in the vertical direction11,14-16, and signatures of incomplete phase mixing in the disk7,12,17,18. Here we report an analysis of the motions of six million stars in the Milky Way disk. We show that the phase-space distribution contains different substructures with various morphologies, such as snail shells and ridges, when spatial and velocity coordinates are combined. We infer that the disk must have been perturbed between 300 million and 900 million years ago, consistent with estimates of the previous pericentric passage of the Sagittarius dwarf galaxy. Our findings show that the Galactic disk is dynamically young and that modelling it as time-independent and axisymmetric is incorrect.

Cystic papillary adenoma of the seminal vesicle.

BACKGROUND: Primary Seminal Vesicle (SV) tumours are a rare entity, with most SV masses representing invasion of the SV by malignancy originating in an adjacent organ, most often the prostate. Previously reported primary SV epithelial tumours have included adenocarcinoma and cystadenoma, with limited prior reports of inracystic papillary structures. CASE PRESENTATION: A 35-year-old male presented with azoospermia, intermittent macroscopic haematuria, and mild right iliac fossa and groin pain. A papillary appearing seminal vesicle mass was found on imaging and seminal vesicoscopy. The mass was robotically excised with diagnosis of benign cystic papillary adenoma made. CONCLUSION: In this manuscript we describe a rare case of a benign cystic papillary adenoma of the seminal vesicle, a unique histological entity differentiated from cystadenoma of the Seminal Vesicle by its papillary component.

Hierarchies of evidence applied to lifestyle Medicine (HEALM): introduction of a strength-of-evidence approach based on a methodological systematic review.

BACKGROUND: Current methods for assessing strength of evidence prioritize the contributions of randomized controlled trials (RCTs). The objective of this study was to characterize strength of evidence (SOE) tools in recent use, identify their application to lifestyle interventions for improved longevity, vitality, or successful aging, and to assess implications of the findings. METHODS: The search strategy was created in PubMed and modified as needed for four additional databases: Embase, AnthropologyPlus, PsycINFO, and Ageline, supplemented by manual searching. Systematic reviews and meta-analyses of intervention trials or observational studies relevant to lifestyle intervention were included if they used a specified SOE tool. Data was collected for each SOE tool. Conditions necessary for assigning the highest SOE grading and treatment of prospective cohort studies within each SOE rating framework were summarized. The expert panel convened to discuss the implications of findings for assessing evidence in the domain of lifestyle medicine. RESULTS AND CONCLUSIONS: A total of 15 unique tools were identified. Ten were tools developed and used by governmental agencies or other equivalent professional bodies and were applicable in a variety of settings. Of these 10, four require consistent results from RCTs of high quality to award the highest rating of evidence. Most SOE tools include prospective cohort studies only to note their secondary contribution to overall SOE as compared to RCTs. We developed a new construct, Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM), to illustrate the feasibility of a tool based on the specific contributions of diverse research methods to understanding lifetime effects of health behaviors. Assessment of evidence relevant to lifestyle medicine requires a potential adaptation of SOE approaches when outcomes and/or exposures obviate exclusive or preferential reliance on RCTs. This systematic review was registered with the International Prospective Register of Systematic Reviews, PROSPERO [CRD42018082148].

Mood, body image, fear of kidney failure, life satisfaction, and decisional stability following living kidney donation: Findings from the KDOC study.

Prior studies demonstrate that most living kidney donors (LKDs) report no adverse psychosocial outcomes; however, changes in psychosocial functioning at the individual donor level have not been routinely captured. We studied psychosocial outcomes predonation and at 1, 6, 12, and 24 months postdonation in 193 LKDs and 20 healthy controls (HCs). There was minimal to no mood disturbance, body image concerns, fear of kidney failure, or life dissatisfaction, indicating no incremental changes in these outcomes over time and no significant differences between LKDs and HCs. The incidence of any new-onset adverse outcomes postdonation was as follows: mood disturbance (16%), fear of kidney failure (21%), body image concerns (13%), and life dissatisfaction (10%). Multivariable analyses demonstrated that LKDs with more mood disturbance symptoms, higher anxiety about future kidney health, low body image, and low life satisfaction prior to surgery were at highest risk of these same outcomes postdonation. It is important to note that some LKDs showed improvement in psychosocial functioning from pre- to postdonation. Findings support the balanced presentation of psychosocial risks to potential donors as well as the development of a donor registry to capture psychosocial outcomes beyond the mandatory 2-year follow-up period in the United States.

Vaginal film for prevention of HIV: using visual and tactile evaluations among potential users to inform product design.

Topical prevention of HIV and other STIs is a global health priority. To provide options for users, developers have worked to design safe, effective and acceptable vaginal dissolving film formulations. We aimed to characterize user experiences of vaginal film size, texture and color, and their role in product-elicited sensory perceptions (i.e. perceptibility), acceptability and willingness to use. In the context of a user-centered product evaluation study, we elicited users' 'first impressions' of various vaginal film formulation designs via visual and tactile prototype inspection during a qualitative user evaluation interview. Twenty-four women evaluated prototypes. Participants considered size and texture to be important for easy insertion. Color was more important following dissolution than prior to insertion. When asked to combine and balance all properties to arrive at an ideal film, previously stated priorities for individual characteristics sometimes shifted, with the salience of some individual characteristics lessening when multiple characteristics were weighted in combination. While first impressions alone may not drive product uptake, users' willingness to initially try a product is likely impacted by such impressions. Developers should consider potential users' experiences and preferences in vaginal film design. This user-focused approach is useful for characterizing user sensory perceptions and experiences relevant to early design of prevention technologies.

Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.

BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Use of an anaesthesia workstation barrier device to decrease contamination in a simulated operating room.

BACKGROUND.: Strategies to achieve reductions in perioperative infections have focused on hand hygiene among anaesthestists but have been of limited efficacy. We performed a study in a simulated operating room to determine whether a barrier covering the anaesthesia workstation during induction and intubation might reduce the risk of contamination of the area and possibly, by extension, the patient. METHODS.: Forty-two attending and resident anaesthetists unaware of the study design were enrolled in individual simulation sessions in which they were asked to induce and intubate a human simulator that had been prepared with fluorescent marker in its oropharynx as a marker of potentially pathogenic bacteria. Twenty-one participants were assigned to a control group, whereas the other 21 performed the simulation with a barrier device covering the anaesthesia workstation. After the simulation, an investigator examined 14 target sites with an ultraviolet light to assess spread of the fluorescent marker of contamination to those sites. RESULTS.: The difference in rates of contamination between the control group and the barrier group was highly significant, with 44.8% (2.5%) of sites contaminated in the control group vs 19.4% (2.6%) of sites in the barrier group ( P <0.001). Several key clinical sites showed significant differences in addition to this overall decrement. CONCLUSIONS.: The results of this study suggest that application of a barrier device to the anaesthesia workstation during induction and intubation might reduce contamination of the intraoperative environment.

Direct and Indirect Costs Following Living Kidney Donation: Findings From the KDOC Study.

Some living kidney donors (LKDs) incur costs associated with donation, although these costs are not well characterized in the United States. We collected cost data in the 12 mo following donation from 182 LKDs participating in the multicenter prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 167, 92%) had one direct cost or more following donation, including ground transportation (86%), health care (41%), meals (53%), medications (36%), lodging (23%), and air transportation (12%). LKDs missed 33 072 total work hours, 40% of which were unpaid and led to $302 175 in lost wages (mean $1660). Caregivers lost $68 655 in wages (mean $377). Although some donors received financial assistance, 89% had a net financial loss in the 12-mo period, with one-third (33%) reporting a loss exceeding $2500. Financial burden was higher for those with greater travel distance to the transplant center (Spearman's ρ = 0.26, p < 0.001), lower household income (Spearman's ρ = -0.25, p < 0.001), and more unpaid work hours missed (Spearman's ρ = 0.52, p < 0.001). Achieving financial neutrality for LKDs must be an immediate priority for the transplant community, governmental agencies, insurance companies, nonprofit organizations, and society at large.

Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis.

BACKGROUND: To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib. METHODS: Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose. RESULTS: Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17). CONCLUSIONS: Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Ten years with colistin: a retrospective case series.

OBJECTIVE: At the Shaare Zedek Medical Center, we have been using colistimethate sodium (CMS) for empiric as well as pathogen-directed treatment. We present our 10-year experience. METHODS: We conducted a retrospective case-series analysis of patients admitted from 1 January 2004 through 1 May 2014 who received at least one dose of CMS. Patient characteristics analysed for all admission for which patients received CMS, included: age, number of re-admissions, admission ward, renal function, disposition and microbiology results. Overall trend in defined daily dose (DDD) for CMS and resistant isolates was analysed. RESULTS: A total of 5603 admissions met inclusion criteria. Patients' mean (±SD) age was 80 ± 14 years, 1162 (48%) of the admissions were from a healthcare facility and 4367 (78%) of the admissions were to general Internal Medicine wards. The median number of hospital admissions per patient was 5, median admission and discharge creatinine (mg/dl) were 1.05 and 1.01, respectively; 2.3% of admissions required first-time dialysis. The discharge rate from the hospital was 58.4%. Excluding intrinsically CMS-resistant gram-negative organisms, bloodstream and urine isolates were 98% and 100% susceptible, respectively. CMS use (DDDs) increased during the study (p for trend = 0.04) without significant increase in incidence of multidrug-resistant organisms. CONCLUSIONS: Colistimethate sodium use at our institution has increased during this 10-year period. Nevertheless, there is no increasing trend in CMS-resistant organisms, 58% of the patients were discharged alive, and we did not observe significant nephrotoxicity in patients prescribed CMS. CMS should be reserved for microbiologically confirmed extensively drug-resistant gram-negative infections.

Predonation Direct and Indirect Costs Incurred by Adults Who Donated a Kidney: Findings From the KDOC Study.

Limited information exists on the predonation costs incurred by eventual living kidney donors (LKDs). Expenses related to completion of the donation evaluation were collected from 194 LKDs participating in the multi-center, prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 187, 96%) reported one or more direct costs, including ground transportation (80%), healthcare (24%), lodging (17%) and air transportation (14%), totaling $101 484 (USD; mean = $523 ± 942). Excluding paid vacation or sick leave, donor and companion lost wages totaled $35 918 (mean = $187 ± 556) and $14 378 (mean = $76 ± 311), respectively. One-third of LKDs used paid vacation or sick leave to avoid incurring lost wages. Few LKDs reported receiving financial support from the transplant candidate (6%), transplant candidate's family (3%), a nonprofit organization (3%), the National Living Donor Assistance Center (7%), or transplant center (3%). Higher total costs were significantly associated with longer distance traveled to the transplant center (p < 0.001); however, total costs were not associated with age, sex, race/ethnicity, household income, marital status, insurance status, or transplant center. Moderate predonation direct and indirect costs are common for adults who complete the donation evaluation. Potential LKDs should be advised of these possible costs, and the transplant community should examine additional strategies to reimburse donors for them.

Disorders of coagulation in pregnancy.

The process of haemostasis is complex and is further complicated in the parturient because of the physiological changes of pregnancy. Understanding these changes and the impact that they have on the safety profile of the anaesthetic options for labour and delivery is crucial to any anaesthetist caring for the parturient. This article analyses current theories on coagulation and reviews the physiological changes to coagulation that occur during pregnancy and the best methods with which to evaluate coagulation. Finally, we examine some of the more common disorders of coagulation that occur during pregnancy, including von Willebrand disease, common factor deficiencies, platelet disorders, the parturient on anticoagulants, and the more rare acute fatty liver of pregnancy, with a focus on their implications for neuraxial anaesthesia.

Learning through simulated independent practice leads to better future performance in a simulated crisis than learning through simulated supervised practice.

BACKGROUND: Anaesthetists may fail to recognize and manage certain rare intraoperative events. Simulation has been shown to be an effective educational adjunct to typical operating room-based education to train for these events. It is yet unclear, however, why simulation has any benefit. We hypothesize that learners who are allowed to manage a scenario independently and allowed to fail, thus causing simulated morbidity, will consequently perform better when re-exposed to a similar scenario. METHODS: Using a randomized, controlled, observer-blinded design, 24 first-year residents were exposed to an oxygen pipeline contamination scenario, either where patient harm occurred (independent group, n=12) or where a simulated attending anaesthetist intervened to prevent harm (supervised group, n=12). Residents were brought back 6 months later and exposed to a different scenario (pipeline contamination) with the same end point. Participants' proper treatment, time to diagnosis, and non-technical skills (measured using the Anaesthetists' Non-Technical Skills Checklist, ANTS) were measured. RESULTS: No participants provided proper treatment in the initial exposure. In the repeat encounter 6 months later, 67% in the independent group vs 17% in the supervised group resumed adequate oxygen delivery (P=0.013). The independent group also had better ANTS scores [median (interquartile range): 42.3 (31.5-53.1) vs 31.3 (21.6-41), P=0.015]. There was no difference in time to treatment if proper management was provided [602 (490-820) vs 610 (420-800) s, P=0.79]. CONCLUSIONS: Allowing residents to practise independently in the simulation laboratory, and subsequently, allowing them to fail, can be an important part of simulation-based learning. This is not feasible in real clinical practice but appears to have improved resident performance in this study. The purposeful use of independent practice and its potentially negative outcomes thus sets simulation-based learning apart from traditional operating room learning.

Can we say what diet is best for health?

Diet is established among the most important influences on health in modern societies. Injudicious diet figures among the leading causes of premature death and chronic disease. Optimal eating is associated with increased life expectancy, dramatic reduction in lifetime risk of all chronic disease, and amelioration of gene expression. In this context, claims abound for the competitive merits of various diets relative to one another. Whereas such claims, particularly when attached to commercial interests, emphasize distinctions, the fundamentals of virtually all eating patterns associated with meaningful evidence of health benefit overlap substantially. There have been no rigorous, long-term studies comparing contenders for best diet laurels using methodology that precludes bias and confounding, and for many reasons such studies are unlikely. In the absence of such direct comparisons, claims for the established superiority of any one specific diet over others are exaggerated. The weight of evidence strongly supports a theme of healthful eating while allowing for variations on that theme. A diet of minimally processed foods close to nature, predominantly plants, is decisively associated with health promotion and disease prevention and is consistent with the salient components of seemingly distinct dietary approaches. Efforts to improve public health through diet are forestalled not for want of knowledge about the optimal feeding of Homo sapiens but for distractions associated with exaggerated claims, and our failure to convert what we reliably know into what we routinely do. Knowledge in this case is not, as of yet, power; would that it were so.

Perigastric appendagitis: CT and clinical features in eight patients.

AIM: To describe perigastric appendagitis (PA) on CT as a new and distinct clinical entity to enable recognition and prevent additional unnecessary investigation or intervention. MATERIALS AND METHODS: Institutional review board approval was obtained and informed consent was waived. Retrospective review of the clinical data and CT findings in eight patients with PA encountered over 10 years at one institution was performed. The English literature was reviewed and summarized. Two experienced abdominal radiologists reviewed the CT images by consensus. RESULTS: Seven of eight patients had moderate to severe epigastric pain for 1­7 days. All eight patients (four men, four women; mean age 44 years, range 33­81 years) had no fever or leukocytosis. All underwent abdominal CT which showed ovoid fat inflammation along the course of the perigastric ligaments (gastrohepatic, gastrosplenic, and falciform). Two had gastric wall thickening. Although the inflammation was correctly described, the specific diagnosis was not made on initial interpretation in five patients. Subsequently, they underwent further diagnostic testing [an upper gastrointestinal examination and hepatobiliary iminodiacetic acid (HIDA) cholescintigraphy, an upper endoscopy and MRI examination, HIDA cholescintigraphy, another CT, and an MRI examination, respectively]. The HIDA cholescintigraphy, upper GI examination, and upper endoscopy examinations were normal. No repeated examination was performed on the other three patients. Pain resolved spontaneously in all within two days. CONCLUSION: Perigastric appendagitis can present with an acute abdomen, which is safely managed conservatively if diagnosed correctly. Radiologists should be aware of the entity to avoid unnecessary intervention, and recognize the CT findings of ovoid fat inflammation in the distribution of the perigastric ligaments.

Brain-derived neurotrophic factor and Rett syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder with autistic features caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), a transcriptional regulatory protein. RTT has attracted widespread attention not only because of the urgent need for treatments, but also because it has become a window into basic mechanisms underlying epigenetic regulation of neuronal genes, including BDNF. In addition, work in mouse models of the disease has demonstrated the possibility of symptom reversal upon restoration of normal gene function. This latter finding has resulted in a paradigm shift in RTT research and, indeed, in the field of neurodevelopmental disorders as a whole, and spurred the search for potential therapies for RTT and related syndromes. In this context, the discovery that expression of BDNF is dysregulated in RTT and mouse models of the disease has taken on particular importance. This chapter reviews the still evolving story of how MeCP2 might regulate expression of BDNF, the functional consequences of BDNF deficits in Mecp2 mutant mice, and progress in developing BDNF-targeted therapies for the treatment of RTT.

Faecal microbiota transplantation for Clostridium difficile infection.

PURPOSE: To review the current clinical literature regarding the use of fecal microbiota transplantation (FMT) for severe and recurrent Clostridium difficile disease (CDAD). BACKGROUND: Clostridium difficile (C. difficile) is a gram positive, spore forming bacteria, and an important nosocomial pathogen causing healthcare associated diarrhoea in hospitalized patients in developed and developing countries. During the past several years, CDAD has become more frequent, severe, refractory, and more likely to relapse. It has become apparent that C. difficile is no longer just a nosocomial infection, with a rising rate of infection in populations not previously affected. Standard treatment regimens and new medications exist, but recurrence rates are high. METHODS: Using PubMed, we conducted a Boolean search with the following medical subject headings (MeSH): Clostridium difficile infection and fecal transplantation or recurrent C. difficile infection. We restricted the search to human studies, published in English, between 2011 through June 1, 2013. RESULTS: There were 104 publications identified. Of those related to FMT, there were 20 clinical reviews, 6 case reports, 3 clinical trials (one, a randomized control trial), and 1 meta-analysis. Since 1958 there have been 36 published reports of FMT for C. difficile infection (CDI) representing 583 patients. Success rates were higher when FMT was administered via colonoscopy (representing the majority of patients, 79.2%). The overall success rate for FMT, regardless of administration method, was 80-98%. CONCLUSION: Fecal microbiota transplantation attempts to restore the normal microbiome of the colon, and has achieved a cure rate reaching more than 90%. Mounting evidence supports the utility of FMT for severe and recurrent cases of CDI. Barriers that will need to be addressed are patient perceptions and fears, standard protocol development, and further clinical trials.

The art and science of chronic disease management come together in a lifestyle-focused approach to primary care.

Changes in patterns of living result in changes in the nature and causes of disease. The industrial revolution of the late 18th century, and the technological revolution of the late 20th century are cases in point. The former was associated with a decline in infectious diseases; the latter with an increase in lifestyle and environmentally induced chronic diseases . Health practices are typically modified to deal with such changes, hence the recent rise in interest in lifestyle-oriented forms of clinical practice.

Variability of fibrinolytic activity in pregnant patients exposed to tissue plasminogen activator: an in vitro study utilizing rotational thromboelastometry.

BACKGROUND: The investigation into the variability of fibrinolysis in obstetric patients is notably limited despite its relevance to postpartum hemorrhage. We investigate an in vitro model of fibrinolysis measured by rotational thromboelastrometry (ROTEM) in maternal blood samples with lysis stimulated by tissue plasminogen activator (tPA). METHODS: Written informed consent was obtained from 19 patients at term pregnancy during admission to the labor and delivery unit. Patients who were taking medication affecting coagulation were excluded. Tissue plasminogen activator was added to whole blood samples to a final concentration of 100 or 220 ng/mL prior to ROTEM testing. RESULTS: The addition of tPA produced high intra-individual fibrinolytic variability for clot firmness and lysis parameters. Patients responded differently to each tPA dose ranging from clot lysis within the range of 0 ng/mL tPA group to complete clot lysis. The coefficient of variation (CV) values for the 220 ng/mL tPA group were: EXTEM MCF 0.510, EXTEM LI30 1.601, FIBTEM MCF 0.349, FIBTEM LI30 2.097. CV values for the 100 ng/mL tPA group were: EXTEM MCF 0.144, EXTEM LI30 1.038, FIBTEM MCF 0.096, FIBTEM LI30 1.238. CONCLUSION: We demonstrate a wide range of fibrinolytic response in the obstetric population to exogeneous tPA. We found subgroups of patients that were very responsive to tPA and insensitive to tPA. This study represents a preliminary exploration into classifying the obstetric fibrinolytic phenotypes. Further research will integrate relevant coagulation factors to establish a predictive model for testing susceptibility to lysis that can be applied at the point of care.