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Changing-look active galactic nuclei (CLAGN) are AGN that change type as their broad emission lines appear or disappear, which is usually accompanied by strong flux changes in their blue featureless continuum. We search for turn-on CLAGN by selecting type-2 AGN from the spectroscopic Six-degree Field Galaxy Survey (6dFGS), whose colours, observed ∼15 yr later by the SkyMapper Southern Survey, are suggestive of type-1 AGN. Starting from 1092 type-2 AGN, we select 20 candidates for follow-up and confirm that 14 of them have changed into type-1 and are thus turn-on CLAGN; further observations reveal 11 more turn-on CLAGN. While our search was not tailored to efficiently discover turn-off CLAGN, we discover two such cases as well. The result suggests a turn-on CLAGN rate of over 3 per cent over ∼15 yr and imply a total CLAGN rate of more than ∼6 per cent over this period. Finally, we present observations of AGN that are atypical for the CLAGN phenomenology, including J1109146 – a type-1 that did not appear as an AGN at all in 6dFGS; J1406507 – the second reported changing-look narrow-line Seyfert 1; and J1340153 – a CLAGN with a change time-scale of 3 months.

Supplemental Digital Content is available in the text., Kidney donation reduces renal function by ≈30% allowing study of the cardiovascular effects of a reduced estimated glomerular filtration rate without comorbidities. We report 5-year results of a longitudinal, parallel-group, blinded end-point study of living kidney donors (n=50) and healthy controls (n=45). The primary end point, left ventricular mass, was measured using cardiac magnetic resonance. Secondary end points, 24-hour ambulatory blood pressure, and pulse wave velocity were measured using validated blood pressure monitors and the SphygmoCor device. Effect sizes were calculated as differences between change from baseline in the donor and control groups. In donors, estimated glomerular filtration rate was 95±15 mL/min per 1.73 m2 at baseline (predonation) and 67±14 mL/min per 1.73 m2 at 5 years. In controls, there was a −1±2 mL/min per 1.73 m2 decline per annum. Change in left ventricular mass at 5 years was not significantly different between donors and controls (mean difference, +0.40 g [95% CI, −4.68 to 5.49] P=0.876), despite an initial increase in mass in donors compared with controls at 12 months. Pulse wave velocity, which increased in donors at 12 months, returned to levels not different from controls at 5 years (mean difference, −0.24 m/s [95% CI, −0.69 to 0.21]). Change in ambulatory systolic blood pressure was not different in donors compared with controls (mean difference, +1.91 mm Hg [95% CI, −2.72 to 6.54]). We found no evidence that the reduction in estimated glomerular filtration rate after kidney donation was associated with a change in left ventricular mass detectable by magnetic resonance imaging at 5 years.

Maternal prenatal stress influences offspring neurodevelopment and birth outcomes including the ratio of males to females born; however, there is limited understanding of what types of stress matter, and for whom. Using a data-driven approach with 27 variables from questionnaires, ambulatory diaries, and physical assessments collected early in the singleton pregnancies of 187 women, 3 latent profiles of maternal prenatal stress emerged that were differentially associated with sex at birth, birth outcomes, and fetal neurodevelopment. Most women (66.8%) were in the healthy group (HG); 17.1% were in the psychologically stressed group (PSYG), evidencing clinically meaningful elevations in perceived stress, depression, and anxiety; and 16% were in the physically stressed group (PHSG) with relatively higher ambulatory blood pressure and increased caloric intake. The population normative male:female secondary sex ratio (105:100) was lower in the PSYG (2:3) and PHSG (4:9), and higher in the HG (23:18), consistent with research showing diminished male births in maternal stress contexts. PHSG versus HG infants were born 1.5 wk earlier (P

SUMMARYWhile molecules that promote the growth of animal cells have been identified, the following question remains: How are growth promoting pathways regulated to specify a characteristic size for each of the different cell types? In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints – mechanisms that restrict cell cycle progression from cells that aresmallerthan theirtarget size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cell’sactualsize and cell’stargetsize. In the present study, we materialize this conceptual distinction by describing experimental assays that discriminately quantify a cell’s target size value. With these assays, we show that a cell’s size and target size are distinct phenotypes that are subject to different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cell’s target size value is regulated by other pathways including FGFR3, ROCK2, and CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, rapamycin does not change the target size that is required for the G1/S transition. The CDK4/Rb pathway has been previously proposed as a putative regulator of target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size were not validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to ‘dial’ higher and lower levels of CDK4 activity. These measurements identified functions of CDK4 on target size that are distinct from other G1 CDKs. UsingC. elegans, we further demonstrate that these influences of CDK4 on size determination functionin vivo. Finally, we propose a model whereby mTORC1, p38, and CDK4 cooperate in a manner that is analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostatdialthat sets the critical target size associated with cell size homeostasis.

Objectives Hepatitis C virus (HCV) infection is a serious health problem in New York City. Although curative treatments are available, many people are out of care. The New York City Department of Health and Mental Hygiene (DOHMH) used surveillance data and various outreach methods to attempt to link to care people diagnosed with HCV infection from 2010 through 2015. Methods We randomly assigned people out of care (ie, no HCV test >6 months after first report) to 4 outreach groups: no outreach (control group); letter only; letter and telephone call; and letter, text message, and telephone call. Three months after outreach ended, we analyzed surveillance data to identify people with a subsequent HCV RNA or genotype test suggesting linkage to care. Results Of 2626 selected people, 199 (7.6%) had a subsequent HCV test. People in all 3 outreach groups had higher odds of a subsequent test than people in the control group (letter only: adjusted odds ratio [aOR] = 1.81 [95% CI, 1.18-2.91]; letter and telephone: aOR = 3.11 [95% CI, 1.67-5.79]; letter, text, and telephone: aOR = 3.17 [95% CI, 1.48-6.51]). People in the letter and telephone group had higher odds of a subsequent test than people in the letter-only group (aOR = 1.72; 95% CI, 1.04-2.74). Most people in the letter and telephone (136/200, 68.0%) and the letter, text, and telephone (71/99, 71.7%) groups could not be reached, primarily because telephone numbers were incorrect or out of service. Conclusion Reaching out to people soon after first report or prioritizing groups in which more recent contact information can be found might improve outcomes of future outreach.

Background The inverse association between estimated glomerular filtration rate (eGFR) and cardiovascular risk is well recognised but not fully explained. Kidney donation is known to reduce renal function by approximately 30% and allows the prospective study of the cardiovascular effects of a reduced eGFR in healthy subjects without confounding comorbidities. We report five year results in a group of kidney donors and healthy controls who underwent extensive cardiovascular assessment. Methods A 5 year longitudinal, parallel group, blinded end-point study of living kidney donors (n=50) and healthy controls (n=45). Participants underwent office and 24-hr ambulatory blood pressure measures, multi-parametric cardiac magnetic resonance imaging (MRI) (3 Tesla), measurement of arterial stiffness (SphygmoCor), carotid intima-media thickness and blood and urine analysis at baseline, one year and 5 years from donation. Results The eGFR in donors at baseline was 95 ± 15ml/min/1.73m2, 65 ± 13ml/min/1.73m2 at one year and 67 ± 14ml/min/1.73m2 at 5 years. Left ventricular (LV) mass was 112g at baseline in both groups and was not different at 5 years (113 ± 31 vs. 115 ± 30, p=0.707). There was also no difference in LV volumes, LV geometry, LV function, T1 times or extracellular volume (ECV) on MRI. Office and ambulatory blood pressures did not differ from controls at any time point. Pulse wave velocity was higher in donors at one year but not significantly different by 5 years. At 5 years, there was no significant differences in the prevalence of a detectable troponin or mean plasma NT pro-BNP. Conclusion The stable reduction in eGFR to levels of 60-70 ml/min/1.73m2 after live kidney donation does not lead to deleterious changes in cardiovascular structure and function or biomarkers of cardiovascular disease at 5 years. Factors associated with kidney disease other than an isolated fall in eGFR are likely to explain the increased cardiovascular risk in patients with chronic kidney disease. Figure A and B: Longitudinal change in LV mass and PWV before and after donation in donors and controls. Black solid lines are means with confidence intervals for donors and dashed lines represent controls. Black squares indicate study visits. A; Left ventricular mass (g) and B; Adjusted pulse wave velocity (m/s) (adjusted for mean arterial pressure and heart rate). Conflict of Interest None

Background and Aims Chronic kidney disease (CKD) is a highly prevalent risk factor for cardiovascular disease with an inverse relationship between estimated glomerular filtration rate (eGFR) and increases in all-cause and cardiovascular mortality. Living kidney donation provides a model to study the cardiovascular effects of a reduced kidney function in previously healthy subjects without comorbidities. We report follow up results in a group of kidney donors and healthy controls who underwent cardiovascular assessment at baseline, 12 months and 5 years after nephrectomy in the CRIB-DONOR studies (NCT01028703, NCT02973607). Method A longitudinal blinded end point study of kidney donors (n=50) and healthy controls (n=45) followed up between May 2017 to May 2019. Participants underwent a cardiac MRI (3.0 Tesla) for assessment of left ventricular (LV) size, mass, systolic function (ejection fraction and 3-dimensional feature tracking) and aortic distensibility. Clinical assessment included; office and 24-hr ambulatory blood pressure measures, measurement of arterial stiffness (SphygmoCor) and blood and urine analysis. Results Mean follow up time was 5.7 ± 0.7 yrs. Mean eGFR in donors was 95 ± 15 ml/min/1.73m2 prior to donation, 65 ±13ml/min/1.73m2 at 12 months and 67 ± 14 ml/min/1.73m2 at 5 years. This compared with an annual decline in eGFR of -1ml/min/1.73m2 in healthy controls. Despite a rise in LV mass at 12 months in the original study, by 5 years, LV mass in donors was no different to controls (113 ± 31g vs. 115 ± 30g, p=0.707). There was also no significant difference in LV volumes or LV geometry. At 5 years, 3D global longitudinal strain (donors -16.2 ± 2.5% vs. controls -14.9 ± 2.1%, p=0.007) and 3D global circumferential strain (donors -19.0 ± 2.5% vs. controls -17.7 ± 2.2%, p=0.004) were marginally greater in donors than controls. Markers of vascular stiffness (pulse wave velocity and augmentation index) were increased in donors compared to controls at 12 months but at 5 years they were not significantly different. No changes in office or ambulatory blood pressure were observed at any time point in donors or controls. At 5 years, uric acid was significantly greater in donors than controls (335 ± 83 µmol/L vs. 276 ± 7, p= Conclusion The reduction in eGFR associated with nephrectomy in living kidney donors in the absence of intrinsic renal disease or comorbidity does not lead to adverse changes in cardiovascular structure and function at 5 years. This study offers reassurance to living kidney donors and the transplant community but should prompt further work into the causes of cardiovascular disease in CKD as we have found no medium term deleterious cardiovascular effects of an isolated reduction in eGFR.

Maternal stress is a risk factor for adverse pregnancy outcomes (APOs). This study evaluates the associations of prenatal stress and APOs with maternal stress years after pregnancy. The 10-item Perceived Stress Scale (PSS) (0–40 range) was completed in the first and third trimesters, and 2–7 years after delivery among a subsample (n = 4161) of nulliparous women enrolled at eight US medical centers between 2010 and 2013 in a prospective, observational cohort study. Demographics, medical history, and presence of APOs (gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preeclampsia (PE), and medically indicated or spontaneous preterm birth (miPTB, sPTB)) were obtained. The associations of prenatal PSS and the presence of APOs with PSS scores years after delivery were estimated using multivariable linear regression. Mean PSS scores were 12.5 (95% CI 12.3, 12.7) and 11.3 (95% CI 11.1, 11.5) in the first and third trimesters respectively and 14.9 (95% CI 14.7, 15.1) 2–7 years later, an average increase of 2.4 points (95% CI 2.2, 2.6) from the start of pregnancy. Regressing PSS scores after delivery on first-trimester PSS and PSS increase through pregnancy showed positive associations, with coefficients (95% CI) of 2.8 (2.7, 3.0) and 1.5 (1.3, 1.7) per 5-point change, respectively. Adding APO indicator variables separately showed higher PSS scores for women with HDP (0.7 [0.1, 1.3]), PE (1.3 [0.6, 2.1]), and miPTB (1.3 [0.2, 2.4]), but not those with GDM or sPTB. In this geographically and demographically diverse sample, prenatal stress and some APOs were positively associated with stress levels 2–7 years after pregnancy. ClinicalTrials.gov Registration number NCT02231398.

Objective To explore the shared experiences of miscarriage using a qualitative analysis of social media posts on Instagram. Methods We performed this qualitative study by collecting text, photos, hashtags, and emoji from 200 Instagram posts on five arbitrarily selected days in 2019. Key eligibility criteria included posts that described a personal experience of miscarriage and that used the hashtag #ihadamiscarriage. Through directed content analysis, our multidisciplinary team conducted open coding to identify common topics in the data, developed a code book, and coded all posts. Twenty-five percent of posts were double-coded by two team members and analyzed for agreement. The codes were organized into overarching themes. Results Intercoder reliability was excellent (kappa 0.95). Themes included medical and physical experiences of miscarriage, social experiences of miscarriage, the emotional spectrum of experiencing a miscarriage, family identity and the effects of miscarriage, and mechanisms of processing and coping through a miscarriage. We observed complex and often conflicted emotional states and noted that the effects of miscarriage were felt for months and years by many Instagram users. Use of social media and disclosure of miscarriage was a source of coping for many users. Conclusion Women post about their miscarriages on social media for a variety of reasons, especially to find support and community and to help break the silence around miscarriage. Health care providers may consider discussing use of this platform as a support and coping mechanism in the setting of pregnancy loss.

Background: Children with long-chain fatty acid β-oxidation disorders (LCFAOD) presenting with clinical symptoms are treated with a specialist infant formula, with medium chain triglyceride (MCT) mainly replacing long chain triglyceride (LCT). It is essential that the safety and efficacy of any new specialist formula designed for LCFAOD be tested in infants and children. Methods: In an open-label, 21-day, phase I trial, we studied the safety of a new MCT-based formula (feed 1) in six well-controlled children (three male), aged 7–13 years (median 9 years) with LCFAOD (very long chain acyl CoA dehydrogenase deficiency [VLCADD], n=2; long chain 3-hydroxyacyl CoA dehydrogenase deficiency [LCHADD], n=2; carnitine acyl carnitine translocase deficiency [CACTD], n=2). Feed 1 (Lipistart; Vitaflo) contained 30% energy from MCT, 7.5% LCT and 3% linoleic acid and it was compared with a conventional MCT feed (Monogen; Nutricia) (feed 2) containing 17% energy from MCT, 3% LCT and 1.1% linoleic acid. Subjects consumed feed 2 for 7 days then feed 1 for 7 days and finally resumed feed 2 for 7 days. Vital signs, blood biochemistry, ECG, weight, height, food/feed intake and symptoms were monitored. Results: Five subjects completed the study. Their median daily volume of both feeds was 720 mL (range 500–1900 mL/day). Feed 1 was associated with minimal changes in tolerance, free fatty acids (FFA), acylcarnitines, 3-hydroxybutyrate (3-HB), creatine kinase (CK), blood glucose, liver enzymes and no change in an electrocardiogram (ECG). No child complained of muscle pain or symptoms associated with LCFAOD on either feed. Conclusions: This is the first safety trial reported of an MCT formula specifically designed for infants and children with LCFAOD. In this short-term study, it appeared safe and well tolerated in this challenging group.

Background Inflammatory breast cancer (IBC) often affects women at a relatively young age. To the authors' knowledge, the rate of BRCA variants among patients with IBC is not known. To determine the association between BRCA status and IBC, the authors evaluated its rate and compared the clinicopathologic characteristics of patients with IBC with those of patients with other breast cancers (non-IBC). Methods Patients who presented at the study institution's cancer genetics program and who underwent BRCA genetic testing were included in the current study. The authors compared clinicopathologic data between patients with IBC and those with non-IBC using propensity score matching to identify predictors. Results A total of 1789 patients who underwent BRCA genetic testing (1684 with non-IBC and 105 with IBC) were included. BRCA pathogenic variants were found in 27.3% of patients with non-IBC and 18.1% of patients with IBC (P = .0384). After propensity score matching, there were no significant differences noted between patients with IBC and those with non-IBC, including the rate of BRCA pathogenic variants (P = .5485). However, a subgroup analysis of the 479 patients with BRCA pathogenic variants demonstrated that patients with IBC (19 patients) were diagnosed at significantly younger ages compared with patients with non-IBC (P = .0244). Conclusions There was no clear association observed between BRCA pathogenic variants and IBC. However, among patients who tested positive for BRCA pathogenic variants, those with IBC were younger at the time of diagnosis compared with those with non-IBC breast cancers. These results confirm that genetic testing is important for patients with IBC who meet the current clinical criteria for genetic testing in breast cancer. Cancer 2018;124:466-74. © 2017 American Cancer Society.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

ContextUp to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.MethodsWe performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.ResultsIn total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.ConclusionAdrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.

BACKGROUND Patients with chronic kidney disease (CKD) are at an increased risk of developing end-stage renal disease (ESRD). We assessed for the first time whether urinary free light chains (FLC) are independently associated with risk of ESRD in patients with CKD, and whether they offer incremental value in risk stratification. MATERIALS AND METHODS We measured urinary FLCs in 556 patients with CKD from a prospective cohort study. The association between urinary kappa/creatinine (KCR) and lambda/creatinine (LCR) ratios and development of ESRD was assessed by competing-risks regression (to account for the competing risk of death). The change in C-statistic and integrated discrimination improvement were used to assess the incremental value of adding KCR or LCR to the Kidney Failure Risk Equation (KFRE). RESULTS 136 participants developed ESRD during a median follow-up time of 51 months. Significant associations between KCR and LCR and risk of ESRD became non-significant after adjustment for estimated glomerular filtration rate (eGFR) and albumin/creatinine ratio (ACR), although having a KCR or LCR >75th centile remained independently associated with risk of ESRD. Neither KCR nor LCR as continuous or categorical variables provided incremental value when added to the KFRE for estimating risk of ESRD at two years. CONCLUSIONS Urinary FLCs have an association with progression to ESRD in patients with CKD which appears to be explained to a degree by their correlation with eGFR and ACR. Levels above the 75th centile do have an independent association with ESRD, but do not improve upon a current model for risk stratification.

Inflammatory breast cancer (IBC) often affects women at a relatively young age. To the authors' knowledge, the rate of BRCA variants among patients with IBC is not known. To determine the association between BRCA status and IBC, the authors evaluated its rate and compared the clinicopathologic characteristics of patients with IBC with those of patients with other breast cancers (non-IBC).Patients who presented at the study institution's cancer genetics program and who underwent BRCA genetic testing were included in the current study. The authors compared clinicopathologic data between patients with IBC and those with non-IBC using propensity score matching to identify predictors.A total of 1789 patients who underwent BRCA genetic testing (1684 with non-IBC and 105 with IBC) were included. BRCA pathogenic variants were found in 27.3% of patients with non-IBC and 18.1% of patients with IBC (P = .0384). After propensity score matching, there were no significant differences noted between patients with IBC and those with non-IBC, including the rate of BRCA pathogenic variants (P = .5485). However, a subgroup analysis of the 479 patients with BRCA pathogenic variants demonstrated that patients with IBC (19 patients) were diagnosed at significantly younger ages compared with patients with non-IBC (P = .0244).There was no clear association observed between BRCA pathogenic variants and IBC. However, among patients who tested positive for BRCA pathogenic variants, those with IBC were younger at the time of diagnosis compared with those with non-IBC breast cancers. These results confirm that genetic testing is important for patients with IBC who meet the current clinical criteria for genetic testing in breast cancer. Cancer 2018;124:466-74. © 2017 American Cancer Society.

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering.AIM: The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure.DESIGN: This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug.

SummaryObjective Most prolactinomas in females are diagnosed during the reproductive age, and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. Design and methods We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed up in a large UK pituitary centre. Information on presentation, management and outcomes was collected. Results Seventeen women with a median age at diagnosis of 63 years (range 52-78) were identified. Headaches and/or visual deterioration were the most commonly reported complaints at detection of the adenoma (47%). Acute pituitary apoplexy was diagnosed at presentation or during follow-up in 18% of the cases. The median serum prolactin was 12 364 mU/L (range 2533-238 479). Macroprolactinomas comprised 94% of the tumours, and 88% of them had supra/parasellar extension. All patients with macroprolactinoma were offered dopamine agonist, and normal prolactin was achieved in 94% of them (median follow-up 91.5 months). Adenoma shrinkage was observed in all women. Improvement or resolution of visual disturbances documented at presentation was observed in 86% of cases. Conclusions The clinical phenotype of prolactinomas diagnosed in the postmenopausal period is characterized by dominance of macroadenomas, with frequent supra/parasellar extension and a relative high rate of acute pituitary apoplexy. In this group of patients, the response of the macroadenomas to dopamine agonists is good.

Squirrelfishes and soldierfishes (Holocentridae) are among the most conspicuous species in the nocturnal reef fish community. However, there is no clear consensus regarding their evolutionary relationships, which is reflected in a complicated taxonomic history. We collected DNA sequence data from multiple single copy nuclear genes and one mitochondrial gene sampled from over fifty percent of the recognized holocentrid species and infer the first species-level phylogeny of the Holocentridae. Our results strongly support the monophyly of the clades Myripristinae (soldierfishes) and Holocentrinae (squirrelfishes). The molecular phylogenies differ with regard to previous hypotheses of relationships within the Myriprisitinae, resolving a clade of cryptic reef associated and deep water non-reef dwelling lineages (Corniger+Plectrypops+Ostichthys) that is the sister lineage to a monophyletic Myripristis. Within Holocentrinae, Neoniphon and Sargocentron are strongly supported as paraphyletic, while Holocentrus is nested within Sargocentron. Using Bayesian ancestral state reconstruction methods, we demonstrate the taxonomically diagnostic characters for Neoniphon and Sargocentron likely represent character states with a complex evolutionary history that is not reflective of shared common ancestry. We propose a new classification for Holocentrinae, recognizing four lineages that are treated as genera: Sargocentron Fowler, 1904, Holocentrus Scopoli, 1777, Flameo Jordan and Evermann, 1898, and Neoniphon Castelnau, 1875.

BackgroundLight's criteria are ratios of pleural fluid to serum total protein (TP), pleural fluid to serum lactate dehydrogenase (LDH) and pleural fluid LDH to the upper reference limit for serum LDH. They are used to classify pleural effusions into an exudate or transudate when pleural fluid protein is 25–35 g/L. We evaluated the impact of between analytical platforms on the classification of pleural effusions using Light's criteria.MethodsLight's criteria were used to classify pleural effusions with fluid TP between 25 and 35 g/L into exudate and transudate. LDH and TP were analysed using an Abbott ARCHITECT c16000 analyser using a lactate to pyruvate method for LDH and two Roche Cobas 800 c702 analysers, one using a lactate to pyruvate method (laboratory B) and one a lactate to pyruvate method (laboratory C).ResultsEighty-three paired serum and pleural fluid samples were analysed. Of these, 44 samples had a pleural fluid TP between 25 and 35 g/L and were classified according to Light's criteria. Classification of pleural fluid into transudate or exudate using different analytical platforms was 82% concordant. The LDH ratio and TP ratio were similar in laboratory B and laboratory C, but these were respectively lower (pConclusionsAlthough Light's criteria are ratios, which should minimise interassay variability, we report 18% discordance between different analytical platforms. The discordance was largely due to the performance of LDH and to a lesser extent protein assays in pleural fluid. Laboratories should be aware that assays may perform differently in serum and pleural fluid.

Background Liquid-chromatography tandem mass spectrometry (LC–MS/MS) has become the method of choice in steroid hormone measurement. However, little information on the mutual agreement of LC–MS/MS methods is available. We compared eight routine unpublished LC–MS/MS methods for the simultaneous measurement of testosterone and androstenedione. Methods Sixty random serum samples from male and female volunteers were analysed in duplicate by eight routine LC–MS/MS methods. We performed Passing–Bablok regression analyses and calculated Pearson's correlation coefficients to assess the agreement of the methods investigated with one published method known to be accurate. Intra-assay CV of each method was calculated from duplicate results, recoveries for each method were calculated from six spiked samples. Furthermore, a CV between the investigated methods was calculated. Results The concentrations ranged from 0.05–1.26 nmol/L, 6.15–24.44 nmol/L and 0.15–4.78 nmol/L for testosterone in females, testosterone in males and androstenedione, respectively. The intra-assay CVs were between 3.7–16.0%, 0.9–5.2% and 1.2–9.5% for testosterone in females, testosterone in males and androstenedione, respectively. The slopes of the regression lines ranged between 0.90–1.25, 0.87–1.24 and 0.94–1.31 for testosterone concentrations in females, all testosterone values and androstenedione, respectively. Inter-method CVs were 24%, 14% and 29% for testosterone for concentrations in females and males and androstenedione, respectively. These compare unfavourably to the variation found earlier in published methods. Conclusion Although most routine LC–MS/MS methods investigated here showed a reasonable agreement, some of the assays showed a high variation. The observed differences in standardization should be taken into account when applying reference values, or should, preferably, be solved.

This paper reflects on the formation of peer groups among street children in Mumbai and upon the author's experience of ethnographic filmmaking with these children. Managing without conventional family structures, these children rely on a network of relations based on friendship, origins and survival. At an early age, they become autonomous social actors, actively seeking social knowledge and carving out their own network of social relations and support. The paper observes that the autonomous nature of street life allows the children to inhabit a seemingly harsh environment in a characteristically playful and imaginative way. It argues that observational filming as a research method is especially well suited to the task of attempting to ‘see’ through the eyes of street children and asserts that in doing so, the street is transformed from a place of deprivation into a vast and open canvas which offers endless possibilities for fun, excitement—and a different sort of education.

Interference in immunoassay caused by endogenous immunoglobulin is a cause of incorrect laboratory results that can drastically affect patient management. Two cases of immunoglobulin interference in serum follicle-stimulating hormone (FSH) assays are presented. These cases illustrate two common mechanisms for false-positive interference in two-site (sandwich) immunoassays. The first case describes a circulating autoimmune FSH immunoglobulin complex (‘macro’-FSH), which has not been previously described for FSH, and the second a cross-linking antibody directed against the assay reagents. Immunoglobulin interference was detected and characterized using a combination of method comparison, immunosubtraction and size exclusion chromatography.

We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). Enzyme assay of D-2-HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D-2-HGA whose enzyme activity was normal did not have mutations. Significantly lower D-2-HG concentrations in body fluids were observed in mutation-positive D-2-HGA patients than in mutation-negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. Accordingly, we suggest a new classification: D-2-HGA Type I associates with D-2-HGDH deficiency, whereas idiopathic D-2-HGA manifests with normal D-2-HGDH activity and higher D-2-HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D-2-HGA patients with diverse genetic loci will be revealed in future studies.

C-terminal binding protein (CtBP) has been shown to bind to a highly conserved five-amino-acid motif (PXDLS) located very close to the C-terminus of adenovirus early region 1A proteins. It has also been demonstrated that amino acids C-terminal and N-terminal to this original proposed binding site contribute to the interaction. However, conflicting evidence has been presented to show that acetylation of an adjacent lysine residue in Ad5E1A may or may not influence binding. It has now been demonstrated here that acetylation of a lysine, equivalent to position 261 in Ad12 E1A and position 285 in Ad5E1A, in a synthetic peptide disrupts the binding to CtBP1 and CtBP2 and alters the K(i) of the peptide, indicative of a reduction in the affinity of the peptide for CtBP1 and CtBP2, but only to a rather limited extent (less than 2-fold). The solution structures of synthetic peptides equivalent to wild-type and acetylated forms of the Ad12 E1A peptide have been determined by proton NMR spectroscopy. The wild-type form of the peptide adopts a series of beta-turns over the region Val(254)-Arg(262). Within the acetylated isoform, the beta-turn conformation is less extensive, Val(260)-Arg(262) adopting a random confirmation. We conclude that secondary structure (beta-turns) and an appropriate series of amino acid side chains over an extended binding site (PXDLSXK) are necessary for recognition by CtBP, acetylation of lysine interfering with both of these features, but not to such an extent as to totally inhibit interaction. Moreover, it is possible that the beta-turn conformation at the C-terminus of AdE1A contributes to binding to alpha importin and nuclear import. Acetylation of lysine (261) could disrupt interaction through structural destabilization as well as charge neutralization and subsequent nuclear localization.