Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been ...licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.
Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of ...HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.
HER2-positive mBC patients with IHC3+ or FISH ≥2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with 89Zr-trastuzumab. 18F2-fluoro-2-deoxy-D-glucose (FDG)–PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2–PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant 89Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load ‘positive’); patterns C and D were considered negative (>50% or all of the tumor load ‘negative’). Early FDG–PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2–PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF).
In the 56 patients analyzed, 29% had negative HER2–PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2–PET/CT were 88%/72% and 83%/96% for early FDG–PET/CT. Combining HER2–PET/CT and FDG–PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months n = 12, 95% confidence interval (CI) 1.4–7.6 from those with a TTF of 15 months (n = 25, 95% CI 9.7–not calculable).
Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1.
NCT01565200.
Gender identity development in adolescence Steensma, Thomas D.; Kreukels, Baudewijntje P.C.; de Vries, Annelou L.C. ...
Hormones and behavior,
July 2013, 2013-Jul, 2013-07-00, 20130701, Letnik:
64, Številka:
2
Journal Article
Recenzirano
This article is part of a Special Issue "Puberty and Adolescence".This article aims to provide an outline of what is currently known on trajectories, and contributing factors to gender identity ...development in adolescence. We give a historical overview of the concept of gender identity, and describe general identity development in adolescence, gender identity development in the general population and in gender variant youth. Possible psychosocial (such as child and parental characteristics) and biological factors (such as the effects of prenatal exposure to gonadal hormones and the role of genetics) contributing to a gender variant identity are discussed.
Studies focusing on a number of psychosocial and biological factors separately, indicate that each of these factors influence gender identity formation, but little is known about the complex interplay between the factors, nor about the way individuals themselves contribute to the process. Research into normative and gender variant identity development of adolescents is clearly lagging behind. However, studies on persons with gender dysphoria and disorders of sex development, show that the period of adolescence, with its changing social environment and the onset of physical puberty, seems to be crucial for the development of a non-normative gender identity.
•We give a historical overview for the concept of gender identity.•We describe what is known about gender identity development in adolescence.•Possible contributing psychosocial and biological factors are discussed.•The period of adolescence seems to be crucial for gender variant adolescents.
The aim of the study was to evaluate psychiatric symptoms among 1022 persons with various disorders of sex development (DSDs).
The study was a European multicenter cross-sectional clinical evaluation ...in six countries. The mean (SD) age of participants was 32.1 (13.4) years. The cohort consisted of 325 individuals with Turner syndrome, 219 individuals with Klinefelter syndrome (KS), female individuals with various XY-DSD conditions (107 with and 67 without androgenization), 87 male individuals with XY-DSD conditions, and 221 female individuals with congenital adrenal hyperplasia. The Hospital Anxiety and Depression Scale, the Short Autism Spectrum Quotient, the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale, and self-reported mental health history were used to assess psychiatric symptoms.
Across the six DSD diagnostic groups, clinical cutoff symptom scores were reached in 19.5% of participants for anxiety, in 7.1% for depression, in 4.1% for attention-deficit/hyperactivity disorder, and in 9.1% for autism. The mean depression and anxiety scores were higher compared with population norms in men with KS and men with XY-DSD. Compared with participants with other DSD conditions, men with KS reported significantly more mental health symptoms. Self-esteem, satisfaction with care, body dissatisfaction, and experiences of shame were associated with psychiatric symptoms in many DSD conditions.
A substantial minority of adults with DSD, with KS in particular, experience psychiatric morbidity. Across DSD conditions, adults may share feelings of shame. Developing a positive self-esteem and body image may be challenging. Multidisciplinary DSD care that involves specialized mental health support can be of important value.
German Clinical Trials Register DRKS00006072.
The prediction of the quaternary structure of biomolecular macromolecules is of paramount importance for fundamental understanding of cellular processes and drug design. In the era of integrative ...structural biology, one way of increasing the accuracy of modeling methods used to predict the structure of biomolecular complexes is to include as much experimental or predictive information as possible in the process. This has been at the core of our information-driven docking approach HADDOCK. We present here the updated version 2.2 of the HADDOCK portal, which offers new features such as support for mixed molecule types, additional experimental restraints and improved protocols, all of this in a user-friendly interface. With well over 6000 registered users and 108,000 jobs served, an increasing fraction of which on grid resources, we hope that this timely upgrade will help the community to solve important biological questions and further advance the field. The HADDOCK2.2 Web server is freely accessible to non-profit users at http://haddock.science.uu.nl/services/HADDOCK2.2.
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•The HADDOCK Web server has been upgraded to use HADDOCK version 2.2.•It supports mixed-type molecules, for example, protein–nucleic acid, such as nucleosomes.•NMR-based pseudocontact shifts and radius of gyration restraints are included.•The multi-body and solvated docking protocol are extended.•The HADDOCK Web server counts over 6000 users and has served more than 100,000 jobs.
Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD.
To ...assess gender change and gender dysphoria in a large sample of individuals with different DSDs.
A cross-sectional study was conducted in 14 European centers with 1,040 participants (717 female-identifying and 311 male-identifying persons and 12 persons identifying with another gender) with different forms of DSD. The cohort (mean age = 32.36 years, SD = 13.57) was divided into 6 major subgroups: women with 45,X DSD and variants (Turner syndrome; n = 325), men with 47,XXY DSD and variants (Klinefelter syndrome; n = 219), women with XY DSD without androgen effects (n = 107) and with androgen effects (n = 63), men with XY DSD (n = 87), and women with 46,XX congenital adrenal hyperplasia (n = 221). Data on psychosexual outcome were gathered by medical interviews and questionnaires.
Gender change and gender dysphoria.
Although gender changes were reported by 5% of participants, only in 1% (3% if those with Klinefelter and Turner syndromes—conditions in which gender issues are not prominent—are excluded) did the gender change take place after puberty and was likely initiated by the patient. 39 participants (4%) reported gender variance: between male and female, a gender other than male or female, or gender queer, alternating gender roles, or a gender expression that differed from the reported gender. This group had lower self-esteem and more anxiety and depression than the other participants.
Clinicians should be aware of and sensitive to the possibility that their patients with DSD not only might have transgender feelings and a desire to change gender, but also identify as different from male or female. The complexity of their feelings might require counseling for some patients.
The study is unique in the large number of participants from many different clinics, with sizable numbers in most subgroups, and in the large number of aspects that were measured. However, the very broadness of the study made it impossible to focus in detail on gender issues. Also, there is a need for instruments specifically measuring gender dysphoria in individuals with DSD that take non-binary genders into account.
To make appropriate gender care possible for people with DSD, the gender-normative and gender-variant development of children with DSD should be studied in longitudinal studies.
Kreukels BPC, Köhler B, Nordenström A, et al. Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. J Sex Med 2018;15:777–785.
In 2016 we carried out a Swift monitoring programme to track the X-ray hardness variability of eight type-I AGN over a year. The purpose of this monitoring was to find intense obscuration events in ...AGN, and thereby study them by triggering joint XMM-Newton, NuSTAR, and HST observations. We successfully accomplished this for NGC 3783 in December 2016. We found heavy X-ray absorption produced by an obscuring outflow in this AGN. As a result of this obscuration, interesting absorption features appear in the UV and X-ray spectra, which are not present in the previous epochs. Namely, the obscuration produces broad and blue-shifted UV absorption lines of Lyα, C iv, and N v, together with a new high-ionisation component producing Fe xxv and Fe xxvi absorption lines. In soft X-rays, only narrow emission lines stand out above the diminished continuum as they are not absorbed by the obscurer. Our analysis shows that the obscurer partially covers the central source with a column density of few 1023 cm-2, outflowing with a velocity of few thousand km s-1. The obscuration in NGC 3783 is variable and lasts for about a month. Unlike the commonly seen warm-absorber winds at pc-scale distances from the black hole, the eclipsing wind in NGC 3783 is located at about 10 light days. Our results suggest that the obscuration is produced by an inhomogeneous and clumpy medium, consistent with clouds in the base of a radiatively driven disk wind at the outer broad-line region of the AGN.
The number of adolescents referred to specialized gender identity clinics for gender dysphoria appears to be increasing and there also appears to be a corresponding shift in the sex ratio, from one ...favoring natal males to one favoring natal females.
We conducted two quantitative studies to ascertain whether there has been a recent inversion of the sex ratio of adolescents referred for gender dysphoria.
The sex ratio of adolescents from two specialized gender identity clinics was examined as a function of two cohort periods (2006–2013 vs. prior years). Study 1 was conducted on patients from a clinic in Toronto, and Study 2 was conducted on patients from a clinic in Amsterdam.
Across both clinics, the total sample size was 748. In both clinics, there was a significant change in the sex ratio of referred adolescents between the two cohort periods: between 2006 and 2013, the sex ratio favored natal females, but in the prior years, the sex ratio favored natal males. In Study 1 from Toronto, there was no corresponding change in the sex ratio of 6,592 adolescents referred for other clinical problems.
Sociological and sociocultural explanations are offered to account for this recent inversion in the sex ratio of adolescents with gender dysphoria. Aitken M, Steensma TD, Blanchard R, VanderLaan DP, Wood H, Fuentes A, Spegg C, Wasserman L, Ames M, Fitzsimmons CL, Leef JH, Lishak V, Reim E, Takagi A, Vinik J, Wreford J, Cohen‐Kettenis PT, de Vries ALC, Kreukels BPC, and Zucker KJ. Evidence for an altered sex ratio in clinic‐referred adolescents with gender dysphoria. J Sex Med 2015;12:756–763.
Over the past decade, the number of people referred to gender identity clinics has rapidly increased. This raises several questions, especially concerning the frequency of performing gender-affirming ...treatments with irreversible effects and regret from such interventions.
To study the current prevalence of gender dysphoria, how frequently gender-affirming treatments are performed, and the number of people experiencing regret of this treatment.
The medical files of all people who attended our gender identity clinic from 1972 to 2015 were reviewed retrospectively.
The number of (and change in) people who applied for transgender health care, the percentage of people starting with gender-affirming hormonal treatment (HT), the estimated prevalence of transgender people receiving gender-affirming treatment, the percentage of people who underwent gonadectomy, and the percentage of people who regretted gonadectomy, specified separately for each year.
6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female) visited our gender identity clinic from 1972 through 2015. The number of people assessed per year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The percentage of people who started HT within 5 years after the 1st visit decreased over time, with almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were identified as experiencing regret.
Because the transgender population is growing, a larger availability of transgender health care is needed. Other health care providers should familiarize themselves with transgender health care, because HT can influence diseases and interact with medication. Because not all people apply for the classic treatment approach, special attention should be given to those who choose less common forms of treatment.
This study was performed in the largest Dutch gender identity clinic, which treats more than 95% of the transgender population in the Netherlands. Because of the retrospective design, some data could be missing.
The number of people with gender identity issues seeking professional help increased dramatically in recent decades. The percentage of people who regretted gonadectomy remained small and did not show a tendency to increase.
Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender Dysphoria Study (1972–2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med 2018;15:582–590.
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