Healthcare experiences of gender diverse Australians: a mixed-methods, self-report survey

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background To date the healthcare experiences of gender diverse Australians have received little attention. Previous international research indicates a range of both negative and positive healthcare experiences amongst this diverse population, with negative experiences being those most frequently reported. Method An online survey was designed to examine the healthcare experiences of gender diverse Australians. The survey included Likert scales asking participants to rate their mental and physical health, and their experiences with psychiatrists, general practitioners and surgeons (in terms of perceived comfort, discrimination and information provision). Open-ended questions provided the opportunity for participants to further elaborate on their experiences. Data were collected between June 2012 and July 2013. Quantitative data analysis was conducted utilising SPSS 17.0, including ANCOVAs and correlations to examine the relationships between variables. Qualitative data were coded by the authors in terms of negative or positive responses and the validity of ratings were assessed utilising Cohen's kappa. Results 110 people assigned male at birth (MAAB) and 78 people assigned female at birth (FAAB) completed two separate surveys. All identified as gender diverse as defined in this paper. 70% of participants had accessed a psychiatrist. Participants MAAB rated their experiences with psychiatrists more highly than participants FAAB. 80% of participants had accessed a general practitioner. Comfort with, and respect from, general practitioners were both positively correlated with mental health, whilst discrimination was negatively correlated with mental health. 42.5% of participants had undertaken sex-affirming surgery. Those who had such surgery reported higher levels of physical and mental health than those who had not undertaken surgery. Participants MAAB reported more positive experiences of surgery than did participants FAAB. Conclusions Findings highlight the need for increased education of medical practitioners in regards to engaging with gender diverse clients

Indigenous Sistergirls’ Experiences of Family and Community

Post print (author accepted) manuscript made available following 12 month embargo from date of publication in accordance with publisher copyright policy. “This is an Accepted Manuscript of an article published by Taylor & Francis in [Australian Social Work] on [9 May 2016], available online: http:// www.tandfonline.com/10.1080/0312407X.2016.1165267"While increasing attention has been paid to the experiences of Indigenous sistergirls over the past decade there still remains a dearth of empirical research on the experiences of this diverse population of Indigenous people. This paper seeks to add to the small body of existing literature by reporting on a thematic analysis of existing media in which 18 sistergirls shared their experiences of family and community. The thematic analysis identified two themes within each of these topics. Specifically, when talking about family, both familial acceptance and rejection were salient themes. When talking about community, both the traditional role of sistergirls in their communities and negative responses from communities were salient themes. The paper concludes by suggesting that increased knowledge about the lives of sistergirls may assist social workers in supporting sistergirls both in their own outreach endeavours, and in providing more culturally competent services

Two Allelic Variants of Aldo-Keto Reductase 1A1 Exhibit Reduced in Vitro Metabolism of Daunorubicin

ABSTRACT: Aldo-keto reductases (AKRs) are a class of NADPH-dependent oxidoreductases that have been linked to metabolism of the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Although widely used, cardiotoxicity continues to be a serious side effect that may be linked to metabolites or reactive intermediates generated in their metabolism. In this study we examine the little known effects of nonsynonymous single nucleotide polymorphisms of human AKR1A1 on the metabolism of these drugs to their alcohol metabolites. Expressed and purified from bacteria using affinity chromatography, the AKR1A1 protein with a single histidine (6x-His) tag exhibited the greatest activity using two test substrates: p-nitrobenzaldehyde (5.09 ؎ 0.16 mol/min/mg of purified protein) and DL-glyceraldehyde (1.24 ؎ 0.17 mol/min/mg). These activities are in agreement with published literature values of nontagged human AKR1A1. The 6x-His-tagged AKR1A1 wild type and allelic variants, E55D and N52S, were subsequently examined for metabolic activity using DAUN and DOX. The tagged variants showed significantly reduced activities (1.10 ؎ 0.42 and 0.72 ؎ 0.47 nmol of daunorubicinol (DAUNol) formed/min/mg of purified protein for E55D and N52S, respectively) compared with the wild type (2.34 ؎ 0.71 nmol/min/mg). The wild type and E55D variant metabolized DOX to doxorubicinol (DOXol); however, the levels fell below the limit of quantitation (25 nM). The N52S variant yielded no detectable DOXol. A kinetic analysis of the DAUN reductase activities revealed that both amino acid substitutions lead to reduced substrate affinity, measured as significant increases in the measured K m for the reduction reaction by AKR1A1. Hence, it is possible that these allelic variants can act as genetic biomarkers for the clinical development of DAUN-induced cardiotoxicity

Tai Chi for osteopenic women: design and rationale of a pragmatic randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Post-menopausal osteopenic women are at increased risk for skeletal fractures. Current osteopenia treatment guidelines include exercise, however, optimal exercise regimens for attenuating bone mineral density (BMD) loss, or for addressing other fracture-related risk factors (e.g. poor balance, decreased muscle strength) are not well-defined. Tai Chi is an increasingly popular weight bearing mind-body exercise that has been reported to positively impact BMD dynamics and improve postural control, however, current evidence is inconclusive. This study will determine the effectiveness of Tai Chi in reducing rates of bone turnover in post-menopausal osteopenic women, compared with standard care, and will preliminarily explore biomechanical processes that might inform how Tai Chi impacts BMD and associated fracture risks.</p> <p>Methods/Design</p> <p>A total of 86 post-menopausal women, aged 45-70y, T-score of the hip and/or spine -1.0 and -2.5, have been recruited from primary care clinics of a large healthcare system based in Boston. They have been randomized to a group-based 9-month Tai Chi program plus standard care or to standard care only. A unique aspect of this trial is its pragmatic design, which allows participants randomized to Tai Chi to choose from a pre-screened list of community-based Tai Chi programs. Interviewers masked to participants' treatment group assess outcomes at baseline and 3 and 9 months after randomization. Primary outcomes are serum markers of bone resorption (C-terminal cross linking telopeptide of type I collagen), bone formation (osteocalcin), and BMD of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry). Secondary outcomes include health-related quality-of-life, exercise behavior, and psychological well-being. In addition, kinetic and kinematic characterization of gait, standing, and rising from a chair are assessed in subset of participants (n = 16) to explore the feasibility of modeling skeletal mechanical loads and postural control as mediators of fracture risk.</p> <p>Discussion</p> <p>Results of this study will provide preliminary evidence regarding the value of Tai Chi as an intervention for decreasing fracture risk in osteopenic women. They will also inform the feasibility, value and potential limitations related to the use of pragmatic designs for the study of Tai Chi and related mind-body exercise. If the results are positive, this will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study.</p> <p>Trial registration</p> <p>This trial is registered in Clinical Trials.gov, with the ID number of NCT01039012.</p

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Fluoxetine during pregnancy: impact on fetal development

Morrison, Janna L; Riggs, K Wayne; Rurak, Dan

Kinetics of Valproic Acid Glucuronidation: Evidence for in Vivo Autoactivation

ABSTRACT: Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450-and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. In the current study we investigate the kinetics of valproic acid glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). After a 100 mg/kg i.v. bolus dose of valproic acid (VPA) to adult sheep (n ‫؍‬ 5), the majority of the dose was recovered in urine as VPAG (ϳ79%). Eadie-Hofstee plots of the VPAG formation rate (calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics and provided estimates of the apparent maximum velocity of an enzymatic reaction (V max app ), the substrate concentration resulting in 50% of V max app (S 50 app ), and Hill coefficient (n) of 2.10 ؎ 0.75 mol/min/kg, 117 ؎ 56 M, and 1.34 ؎ 0.14, respectively. Comparable estimates of V max app (2.63 ؎ 0.33 mol/min/kg), S 50 app (118 ؎ 53 M), and n (2.06 ؎ 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under certain experimental conditions and confirm its relevance. The classic hyperbolic Michaelis-Menten equation has long been used to characterize the in vitro kinetics of enzyme-catalyzed reactions. More recently, cytochrome P450 (P450)-catalyzed enzymatic reactions that exhibit sigmoidal kinetics have been described in the literature. Notable examples of this type of kinetic behavior include P450 3A4-catalyzed oxidation of testosterone Valproic acid (2-propylpentanoic acid, VPA) is a broad-spectrum anticonvulsant with a unique branched-chain fatty acid structure 1380 proic acid is unique in that high doses of the compound can be administered such that saturation of its elimination (glucuronidation) occurs in vivo, thus allowing for full characterization of kinetic parameters for its metabolism in vivo. This ability to characterize VPA glucuronidation kinetics in vivo provided a unique opportunity for us to investigate whether the autoactivation kinetics for VPA glucuronidation can be observed in vitro in liver microsomes and, if so, whether this would translate to the in vivo situation. Thus, the objective of the studies described in this manuscript was to investigate the occurrence of sigmoidal/autoactivation kinetics for VPA glucuronidation in vitro and in vivo in sheep. Materials and Methods In Vivo Animal Experiments. Five Dorset Suffolk cross-bred ewes, with a body weight of 61.9 Ϯ 7.3 kg (mean Ϯ S.D.) were surgically prepared with a minimum of 3 days before experimentation. Polyvinyl catheters (Dow Corning, Midland, MI) were implanted in a femoral artery and vein (catheter i.d. 1.02 mm and o.d. 2.16 mm) as described by Unbound plasma concentrations of VPA were determined ex vivo in all adult sheep plasma samples using an ultrafiltration procedure as described by In Vitro Valproic Acid Glucuronidation Kinetics. The glucuronidation kinetics of valproic acid were examined in pooled sheep liver microsomes (pool of 10) (XenoTech LLC, Lenexa, KS). The kinetics of VPA glucuronidation was determined under the following incubation conditions: VPA (5-640 M), 0.5 mg/ml microsomal protein, 2.5 mM MgCl 2 , 5 mM saccharolactone, alamethicin (10 g/mg protein), and 3 mM UDP-glucuronic acid (SigmaAldrich) in 100 mM phosphate buffer (pH 7.5). The total incubation volume was 200 l. All contents of each incubation, with the exception of UDPglucuronic acid, were preincubated for 5 min at 37°C. After the preincubation period, reactions were initiated by the addition of UDP-glucuronic acid. Reactions were terminated at 20 min by the addition of 200 l of ice-cold acetonitrile containing the internal standard (diclofenac at 2 M final concentration; Sigma-Aldrich) followed by thorough vortex mixing. The resulting samples were centrifuged at 2000g for 10 min at 4°C, and 10 l of the supernatant was injected into a liquid chromatograph coupled with a tandem mass spectrometer for quantitation of VPAG. All reactions were performed in triplicate. In preliminary experiments, reactions performed under the described conditions were linear with respect to both microsomal protein concentration and incubation time (data not shown). VPAG was quantitated using a modification of a liquid chromatographytandem mass spectrometry method described previously by San Jose, CA). Samples were injected by a Shimadzu SIL-HTc autosampler (4°C) onto a Waters Symmetry C 18 column (50 mm ϫ 2 mm i.d.; Waters, Determination of Unbound Valproic Acid in Sheep Liver Microsomes. The unbound fraction of VPA in pooled sheep liver microsomes under in vitro incubation conditions was determined by ultracentrifugation using [ 14 C]VPA (valproic acid, [carboxyl-14 C], sodium salt; American Radiolabeled Chemicals, St. Louis, MO). Experiments were performed at 5 and 700 M VPA to span the full range of concentrations used in the in vitro studies examining VPA glucuronidation kinetics. The determination of the VPA unbound fraction in sheep liver microsomes was performed under the following incubation conditions: VPA (5 and 700 M), 0.5 mg/ml microsomal protein, 2.5 mM MgCl 2 , alamethicin (10 g/mg microsomal protein), and 5 mM saccharolactone in 100 mM phosphate buffer (pH 7.4). The total incubation volume was 4 ml. After an incubation period of 30 min at 37°C, 1-ml aliquots of each sample were transferred in triplicate to centrifuge tubes (11 ϫ 34 mm polycarbonate tubes; Beckman Coulter, Fullerton, CA), and samples were centrifuged at 100,000 rpm for 3 h using an Optima TLX ultracentrifuge (Beckman Coulter). Radioactivity content was determined in the supernatant from the samples after centrifugation and in the original microsomal incubation before centrifugation using a Tri-Carb 3100 TR liquid scintillation analyzer (PerkinElmer Life and Analytical Sciences, Boston, MA). The fraction unbound was calculated as the ratio of the average radioactivity measured in the supernatant layers (unbound fraction) to that in the initial microsomal incubate before centrifugation. Pharmacokinetic and Enzyme Kinetic Analyses. In vivo estimates of apparent Hill (V max app , S 50 app , and n) parameters for overall VPA elimination from plasma were obtained through fitting of individual unbound plasma concentration-time profiles using SAAM II V1.2 (The SAAM Institute Inc., Seattle, WA). Unbound plasma concentration-time profiles were fit to a oneor two-compartment model with elimination described by either the MichaelisMenten (eq. 1) or Hill equation (eq. 2), where v is the rate of elimination, V max app is the apparent maximum rate of elimination, C is the substrate concentration, K m app /S 50 app is the apparent substrate concentration resulting in an elimination rate equal to 50% of V max app , and n is the Hill coefficient. A two-compartment model with elimination described by the Hill equation provided the best &quot;fit&quot; of the data from adult animals compared with a simpler one-compartment model with similar elimination characteristics. Model selection was based upon a lower Aikake&apos;s information criterion In vivo estimates of kinetic parameters for VPA glucuronidation from urinary excretion data were determined by fitting v (urinary excretion rate of the glucuronide metabolite) versus C mid (unbound VPA plasma concentration at the midpoint of the urine collection interval) data to the Hill equation . C mid , v, and n are as defined above, V max app is the apparent maximal formation rate of VPAG, and S 50 app is the substrate concentration resulting in 50% of V max app . The fitting to the Hill equation rather than to the classic Michaelis-Menten equation was determined on the basis of the distinct shape of the Eadie-Hofstee plots and by minimization of the sum of squares of residuals and the standard error of parameter estimates when data were fitted to the Hill equation. Datasets were individually fit for each animal using GraphPad Prism V4.02 (GraphPad Software Inc., San Diego, CA). Rates of VPAG formation versus VPA incubation concentrations from in vitro enzyme kinetic experiments using pooled sheep liver microsomes were fit to the Hill equation using GraphPad Prism V4.02 as described above for the in vivo urine data. The VPA incubation concentration substituted for C mid when data from the in vitro experiment were fitted. Simulations. Simulations of the two-compartment model with elimination described by the Hill or Michaelis-Menten equation were performed using SAAM II V1.2. Values of V max app (3.09 mol/min/kg), K m app , or S 50 app (208 M) used in simulations were calculated from estimates previously reported by Results Urinary Recovery of VPA Dose. The recovery of VPA and its metabolites in urine after a 100 mg/kg i.v. dose is presented in In Vivo Estimation of V max app , S 50 app , and n of Overall VPA Elimination from Plasma. Unbound plasma concentration-time profiles were fitted to a two-compartment model with elimination from the central compartment governed by the Hill equation. Unbound concentration-time profiles from individual animals along with their model-predicted plasma profiles are presented in a Includes the following VPA metabolites; 2-n-propyl-2-pentenoic acid, 2-n-propyl-3-pentenoic acid, 2-n-propyl-4-pentenoic acid, 2-n-propyl-3-oxopentanoic acid, 2-n-propyl-4-oxopentanoic acid, 3-hydroxy-VPA, 4-hydroxy-VPA, 5-hydroxy-VPA, 2-propylsuccinic acid, and 2-propylglutaric acid. WONG ET AL. elimination. These estimates are comparable to estimates generated using VPAG urinary excretion data In Vivo Estimation of Apparent V max app , S 50 app , and n of VPA Glucuronidation from Urinary Excretion Data. A condition for estimating the apparent kinetic parameters of VPA glucuronidation using urine data is that the appearance of VPAG in urine is formation rate-limited, as opposed to elimination rate-limited Eadie-Hostee plots of v versus v/C mid for individual animals are shown in Discussion The in vitro kinetics of enzyme-catalyzed reactions is commonly characterized by the hyperbolic Michaelis-Menten equation. Sigmoidal or autoactivation kinetics are distinguished from Michaelis-Menten kinetics by rate-substrate concentration profiles with initial lags at lower concentrations and result in characteristic curved Eadie-Hofste