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Christoph U Correll,1–3 Thomas Brevig,4 Cecilia Brain4 1The Zucker Hillside Hospital, Department of Psychiatry, Glen Oaks, NY, USA; 2The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; 3Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Child and Adolescent Psychiatry, Berlin, Germany; 4H. Lundbeck A/S, Copenhagen, DenmarkCorrespondence: Christoph U CorrellThe Zucker Hillside Hospital, Psychiatry Research, 75–59 263rd Street, Glen Oaks, NY 11004, USATel +1 718 470-4812Fax +1 718 343-1659Email ccorrell@northwell.eduObjective: To explore and describe potential subgroups within the treatment-resistant schizophrenia (TRS) population, using data from a survey of US psychiatrists.Methods: Psychiatrists completed an online survey of demographic/clinical characteristics and treatment history for two of their patients with TRS. Patients were stratified according to number of suicide attempts, number of hospitalizations, employment status, and TRS onset time frame.Results: Of the 408 patients with TRS described by psychiatrists, 37.5% had ≥1 suicide attempt, 78.9% had ≥2 hospitalizations, 74.5% were unemployed, 45.0% had TRS onset within 5 years of first treatment (a further 8.0% had TRS from first treatment), and 31.5% had TRS onset after 5 years (15.5% unknown). Patients with ≥1 (vs 0) suicide attempts had statistically significantly more psychiatric (3.6 vs 2.2) and physical (2.2 vs 1.6) comorbidities. Patients with ≥2 (vs ≤1) hospitalizations were statistically significantly more likely to have hallucinations, conceptual disorganization, social withdrawal, and cognitive dysfunction, and had more psychiatric (3.0 vs 1.9) and physical (2.0 vs 1.1) comorbidities. Unemployed (vs employed) patients were statistically significantly more likely to have delusions, hallucinations, blunted affect, social withdrawal, and cognitive dysfunction, and had more psychiatric (2.9 vs 2.3) and physical (2.1 vs 1.2) comorbidities. Patients with TRS onset ≤5 (vs >5) years were statistically significantly younger (35.0 vs 43.7 years), less likely to have hallucinations and social withdrawal, and had fewer psychiatric (2.6 vs 3.3) and physical (1.7 vs 2.3) comorbidities.Conclusions: Greater clinical burden in TRS is associated with greater illness severity and chronicity markers, suggesting a dimensional gradient from non-TRS to mild–moderate and more severe forms of TRS. Time to onset of TRS may have implications for outcomes, with data indicating greater burden in those with late-onset TRS. Accumulation of illness over time may be more important than time to onset.Keywords: clinical burden, demography, psychiatry, schizophrenia, surveys and questionnaires, treatment resistance

Peter M Haddad,1,2 Cecilia Brain,3,4 Jan Scott5,6 1Neuroscience and Psychiatry Unit, University of Manchester, Manchester, 2Greater Manchester West Mental Health NHS Foundation Trust, Salford, UK; 3Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, 4Nå Ut-teamet, Psychosis Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden; 5Academic Psychiatry, Institute of Neuroscience, Newcastle University, 6Centre for Affective Disorders, Institute of Psychiatry, London, UK Abstract: Nonadherence with medication occurs in all chronic medical disorders. It is a particular challenge in schizophrenia due to the illness's association with social isolation, stigma, and comorbid substance misuse, plus the effect of symptom domains on adherence, including positive and negative symptoms, lack of insight, depression, and cognitive impairment. Nonadherence lies on a spectrum, is often covert, and is underestimated by clinicians, but affects more than one third of patients with schizophrenia per annum. It increases the risk of relapse, rehospitalization, and self-harm, increases inpatient costs, and lowers quality of life. It results from multiple patient, clinician, illness, medication, and service factors, but a useful distinction is between intentional and unintentional nonadherence. There is no gold standard approach to the measurement of adherence as all methods have pros and cons. Interventions to improve adherence include psychoeducation and other psychosocial interventions, antipsychotic long-acting injections, electronic reminders, service-based interventions, and financial incentives. These overlap, all have some evidence of effectiveness, and the intervention adopted should be tailored to the individual. Psychosocial interventions that utilize combined approaches seem more effective than unidimensional approaches. There is increasing interest in electronic reminders and monitoring systems to enhance adherence, eg, Short Message Service text messaging and real-time medication monitoring linked to smart pill containers or an electronic ingestible event marker. Financial incentives to enhance antipsychotic adherence raise ethical issues, and their place in practice remains unclear. Simple pragmatic strategies to improve medication adherence include shared decision-making, regular assessment of adherence, simplification of the medication regimen, ensuring that treatment is effective and that side effects are managed, and promoting a positive therapeutic alliance and good communication between the clinician and patient. These elements remain essential for all patients, not least for the small minority where vulnerability and risk issue dictate that compulsory treatment is necessary to ensure adherence.Keywords: adherence, nonadherence, antipsychotics, schizophrenia, long-acting injections, relapse, risk factors

Xiao-Li Meng's recent article 'Desired and Feared--What Do We Do Now and Over the Next 50 Years?' (2009) was of particular interest to me as a former undergraduate statistics major and as an Associate Professor who teaches 12 sections of introductory statistics annually at Montgomery College, a two-year college in Montgomery County, Maryland (an adjoining county to Washington, D.C.). I approach my comments from these perspectives as I believe that these groups very much need to be represented/addressed in the discussion of Meng's observations and proposals. My remarks are also influenced by a Washington Post article published during the 2009 Joint Statistical Meetings that referred to statisticians as 'superheroes,' described some of the challenges we face, and ultimately presented a favorable light (in my opinion) on our discipline. KEY WORDS: Introductory statistics; Statistical education; Two-year college; Undergraduate education.

The evolution of gender dimorphism is proposed as a means of restoring outcrossing after polylpoidization causes the loss of self-incompatibility. The intraspecific variation is examined in floral morphology and DNA content in populations of Lycium californicum to determine correlations between sexual system and cytotype.

A timescale, when used carefully and appropriately, is the most efficient tool for understanding the long-term effects of carbon dioxide gas emissions on the atmosphere. Timescales provide general rules of thumb that are useful in formulating guidelines for the treatment of carbon dioxide and of other greenhouse gases. Unfortunately, timescales are often misused because scientists have not fully considered timescales for greenhouse gases.

Mitogen-activated protein kinase (MAPK) and MAPK kinase (MAPKK) can be rapidly activated by stimulating aortic smooth muscle cells using platelet derived growth factor BB homodiner (PDGF-BB). PDGF-BB-stimulated MAPKK and MAPK activation are inhibited by prostaglandin E2, isoproterenol, cholera toxin and forskolin. A study records the interactions between the PKA pathway and the growth factor-activated MAPK cascade.

Researchers isolated a fourth Ewing sarcoma-FLI1 gene (EWS-FLI1) fusion cDNA that is structurally different from the three patterns earlier outlined. Other patterns of this fusion were transduced into NIH 3T3 cells to discover the transforming action of the gene. Neuroectodermal and hematopoietic originated tumors were shown to develop from the formation of chimeric transcription factors, hinting that this is common in the development of human cancer.

Hypophosphataemic rickets (HR) is usually secondary to renal phosphate wasting but may occur secondary to reduced intake or absorption of phosphate. We describe a series of cases of HR associated with the use of Neocate®, an amino-acid based formula (AAF). A retrospective review of cases with HR associated with AAF use presenting to centres across the United Kingdom. 10 cases were identified, over a 9 month period, all associated with Neocate® use. The age at presentation was 5 months to 3 years. The majority (8/10) were born prematurely. Gastro oesophageal reflux disease (6/10) was the most frequent indication for AAF use. Radiologically apparent rickets was observed after a median of 8 months (range 3–15 months) of exclusive Neocate® feed. The majority (7/10) were diagnosed on the basis of incidental findings on radiographs: rickets (6/10) or fracture with osteopenia (5/10). All patients had typical biochemical features of HR with low serum phosphate, high alkaline phosphatase, normal serum calcium and 25 hydroxyvitamin D. However, in all cases the tubular reabsorption of phosphate (TRP) was ≥96%. Phosphate supplementation resulted in normalisation of serum phosphate within 1–16 weeks, and levels remained normal only after Neocate® cessation. In patients with sufficient follow up duration (4/10), normalisation of phosphate and radiological healing of rickets was noted after 6 months (range: 6–8 months) following discontinuation of Neocate®. The presence of a normal TRP and resolution of hypophosphataemia and rickets following discontinuation of Neocate® indicates this is a reversible cause likely mediated by poor phosphate absorption. Close biochemical surveillance is recommended for children on Neocate®, especially in those with gastrointestinal co-morbidities, with consideration of a change in feed or phosphate supplementation in affected children. [ABSTRACT FROM AUTHOR]

Background: Increased adiposity is a risk factor for multiple sclerosis (MS) and is associated with increased disability scores. Adipokines may mediate the effects of adiposity on MS disease course. Objective: The objective of this study is to examine the association between the adipokines (leptin and fatty acid binding protein-4, FABP4) and clinical course in individuals with MS. Methods: Subjects (18–65 years) with relapsing-remitting MS or clinically isolated syndrome and <10 year disease duration were selected from a longitudinal clinical study. Cross-sectional and longitudinal models assessed the relationship between two adipokines (leptin and FABP4) and disease severity in women and men, adjusting for age, disease duration and disease type, Vitamin D level, testosterone level, and as well by body mass index (BMI). Results: Mean age of subjects (N = 163, 56% women) was 39.3 years. Higher FABP4 levels were associated with higher Expanded Disability Status Scale (EDSS) scores in women in both univariate and multivariate analyses (odds ratio: 1.30; p = 0.005). In men, higher FABP4 level was significantly associated with change in EDSS over time (estimate: 0.0062; p = 0.035). We found no association of FABP4 levels with time to next relapse or a measure of processing speed. Conclusion: FABP4 levels may be associated with increased disability in both men and women with MS independent of effects of BMI and other hormones. Future studies should expand these analyses and further explore downstream mechanisms of adiposity-related effects in MS. [ABSTRACT FROM AUTHOR]

Background: In patients with multiple endocrine neoplasia type 2 (MEN2) syndrome, genetic testing offers early diagnosis, stratifies the risk of developing medullary thyroid cancer (MTC) and informs the timing of thyroidectomy. The efficacy of treatment, which depends on timely and safe surgery, is not well established. Methods: This was a retrospective review of diagnostic and clinicopathological outcomes of prophylactic thyroidectomy in children with MEN2 between 1995 and 2013 in the UK. American Thyroid Association (ATA) 2009 guidelines were used as a benchmark for adequate treatment. Results: Seventy‐nine children from 16 centres underwent total thyroidectomy. Thirty‐eight patients (48 per cent) underwent genetic testing and 36 (46 per cent) had an operation performed above the age recommended by the ATA 2009 guidelines; pathology showed MTC in 30 patients (38 per cent). Late surgery, above‐normal preoperative calcitonin level and MTC on pathology correlated with late genetic testing. Twenty‐five children had lymphadenectomy; these patients had more parathyroid glands excised (mean difference 0·61, 95 per cent c.i. 0·24 to 0·98; P = 0·001), and were more likely to have hypocalcaemia requiring medication (relative risk (RR) 3·12, 95 per cent c.i. 1·54 to 6·32; P = 0·002) and permanent hypoparathyroidism (RR 3·24, 1·29 to 8·11; P = 0·010) compared with those who underwent total thyroidectomy alone. Age did not influence the development of complications. Conclusion: Late genetic testing may preclude age‐appropriate surgery, increasing the risk of operating when MTC has already developed. Early genetic testing and age‐appropriate surgery may help avoid unnecessary lymphadenectomy and improve outcomes. [ABSTRACT FROM AUTHOR]