Toward a Diagnostic Score in Cushing's Syndrome

Cushing's syndrome (CS) is a classical rare disease: it is often suspected in patients who do not have the disease;at the same time, it takes a mean of 3 years to diagnose CS in affected individuals. The main reason is the extreme rarity (1-3/million/year) in combination with the lack of a single lead symptom. CS has to be suspected when a combination of signs and symptoms is present, which together make up the characteristic phenotype of cortisol excess. Unusual fat distribution affecting the face, neck, and trunk;skin changes including plethora, acne, hirsutism, livid striae, and easy bruising;and signs of protein catabolism such as thinned and vulnerable skin, osteoporotic fractures, and proximal myopathy indicate the need for biochemical screening for CS. In contrast, common symptoms like hypertension, weight gain, or diabetes also occur quite frequently in the general population and per se do not justify biochemical testing. First-line screening tests include urinary free cortisol excretion, dexamethasone suppression testing, and late-night salivary cortisol measurements. All three tests have overall reasonable sensitivity and specificity, and first-line testing should be selected on the basis of the physiologic conditions of the patient, drug intake, and available laboratory quality control measures. Two normal test results usually exclude the presence of CS. Other tests and laboratory parameters like the high-dose dexamethasone suppression test, plasma ACTH, the CRH test, and the bilateral inferior petrosal sinus sampling are not part of the initial biochemical screening. As a general rule, biochemical screening should only be performed if the pre-test probability for CS is reasonably high. This article provides an overview about the current standard in the diagnosis of CS starting with clinical scores and screenings, the clinical signs, relevant differential diagnoses, the first-line biochemical screening, and ending with a few exceptional cases

Real-world effect of antidepressants for depressive disorder in primary care: protocol of a population-based cohort study

Introduction: Clinical guidelines recommend antidepressants as the first line of treatment for adults with moderate-to-severe depression. Randomised trials provide the best evidence on the comparative effectiveness of antidepressants for depression, but are limited by a short follow-up and a highly selected population. We aim to conduct a cohort study on a large database to assess acceptability, efficacy, safety and tolerability of antidepressant monotherapy in people with depressive disorder in primary care.Methods and analysis: This is a protocol for a cohort study using data from the QResearch primary care research database, which is the largest general practice research database in the UK. We will include patients registered for at least 1 year from 1 January 1998, diagnosed with a new episode of depression and on antidepressant and a comparison group not on antidepressant. The exposure of interest will be treatment with antidepressant medications. Our outcomes will be acceptability (treatment discontinuation due to any cause), efficacy (clinical response and remission); safety (adverse events (AEs) and all-cause mortality); and tolerability (dropouts due to any AE) measured at 2 months, 6 months and 1 year. For each outcome, we will estimate the absolute risks for all antidepressants, and relative effects between antidepressants using Cox’s proportion hazards models. We will calculate HRs and 99.9% CIs for each outcome of interest.Discussion: The main limitation is the observational nature of our study, while the major strengths include the large representative population contained in QResearch and the possibly high generalisability

The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2‐Year Follow‐Up Study

Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long‐term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide (PINP), alkaline bone phosphatase, CTX‐I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex‐, age‐, and body mass index (BMI)‐matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T‐score = −1.4 ± 1.1). Two years after successful surgery, the T‐score had improved in 78% of patients (mean T‐score 2 years postoperatively −1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX‐I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three‐ to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients

Plasma steroid profiles in subclinical compared to overt adrenal Cushing's syndrome

CONTEXT Diagnosis of subclinical adrenal hypercortisolism is based on several tests of the hypothalamic-pituitary-adrenal axis to establish mild alterations of cortisol secretion and dysregulated cortisol physiology. OBJECTIVE This study assessed whether plasma steroid profiles might assist diagnosis of subclinical Cushing's syndrome (SC). DESIGN Retrospective cross-sectional study. SETTING Two tertiary medical centers. PATIENTS Two hundred and eight patients were tested for hypercortisolism among whom disease was excluded in 152 and confirmed in 21 with overt clinical Cushing's syndrome due to adrenal tumors (AC) compared to 35 with SC. Another 277 age- and gender-matched hypertensive and normotensive volunteers were included for reference. MAIN OUTCOME MEASURES Panel of 15 plasma steroids measured by mass spectrometry with classification by discriminant analysis. RESULTS Patients with SC showed lower (P<0.05) plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone-sulfate than subjects without SC. The largest increases (P<0.001) in plasma steroids among patients with SC were observed for 11-deoxycortisol and 11-deoxycorticosterone. Nevertheless, concentrations of 11-deoxycorticosterone, 11-deoxycortisol and pregnenolone in patients with AC were higher (P<0.05) than in those with SC. Patients with SC or AC could be distinguished from subjects without disease using the above combination of steroids as precisely as with use of measurements of serum cortisol after dexamethasone. The steroid combination provided superior diagnostic performance compared to each of the other routine biochemical tests. CONCLUSIONS Distinct plasma steroid profiles in patients with SC may provide a simple and reliable screening method for establishing the diagnosis

Engineering Anomalously Large Electron Transport in Topological Semimetals

Anomalous transport of topological semimetals has generated significant interest for applications in optoelectronics, nanoscale devices, and interconnects. Understanding the origin of novel transport is crucial to engineering the desired material properties, yet their orders of magnitude higher transport than single-particle mobilities remain unexplained. This work demonstrates the dramatic mobility enhancements result from phonons primarily returning momentum to electrons due to phonon-electron dominating over phonon-phonon scattering. Proving this idea, proposed by Peierls in 1932, requires tuning electron and phonon dispersions without changing symmetry, topology, or disorder. This is achieved by combining de Haas - van Alphen (dHvA), electron transport, Raman scattering, and first-principles calculations in the topological semimetals MX$_2$ (M=Nb, Ta and X=Ge, Si). Replacing Ge with Si brings the transport mobilities from an order magnitude larger than single particle ones to nearly balanced. This occurs without changing the crystal structure or topology and with small differences in disorder or Fermi surface. Simultaneously, Raman scattering and first-principles calculations establish phonon-electron dominated scattering only in the MGe$_2$ compounds. Thus, this study proves that phonon-drag is crucial to the transport properties of topological semimetals and provides insight to further engineer these materials.Comment: 12 pages, 5 figure

Mental health issues in unaccompanied refugee minors

Previous studies about unaccompanied refugee minors (URMs) showed that they are a highly vulnerable group who have greater psychiatric morbidity than the general population. This review focuses on mental health issues among URMs. Articles in databases PsycINFO, Medline and PubMed from 1998 to 2008 addressing this topic were reviewed. The literature had a considerable emphasis on the assessment of PTSD symptoms. Results revealed higher levels of PTSD symptoms in comparison to the norm populations and accompanied refugee minors. In several studies, age and female gender predicted or influenced PTSD symptoms. The existing literature only permits limited conclusions on this very hard to reach population. Future research should include the analysis of long-term outcomes, stress management and a more thorough analysis of the whole range of psychopathology. Additionally, the development of culturally sensitive norms and standardized measures for diverse ethnic groups is of great importance

‘‘The Soldiers Came to the House’’: Young Children’s Responses to The Colour of Home

This article begins by reflecting on the present refugee crisis and its relevance to children in the UK. It identifies the need for teaching about the refugee experience to young children and argues that literature can provide a conduit for this. Sincethemillenniumtherehasbeenarapidincreaseinthenumberofbookspublished forchildren whichtake thisastheir theme, aimed atever-youngerreaders.Takingasa case study The Colour of Home by Mary Hoffman, a picturebook commonly used in lower primary classrooms, the article considers how this text promotes understanding and validates the circumstances of refugees. It closely examines the motivations and aims of the writer, how the book was mediated by teachers in the primary classroom, and how refugee and non-refugee children read and responded to it. Findings are presented from an interview with Mary Hoffman herself, juxtaposed with data from threeclassroomssuggestingthatpupilsgainedvaluableinsightintoacomplicatedand controversial issue. However the research concludes that viewing children through a refugee/non-refugee binary was reductive in not recognising the multi-layered nuances of meaning which were constructed by young readers who brought to bear a wide variety of individual life and family experiences. Furthermore, teachers in the study played a powerful role in mediating the texts when sharing them in the classroom, and devised a selection of stimulating resources to provoke reader response in terms of empathy, ‘‘social action’’, and some critical literacy