Recent trends in primary-care antidepressant prescribing to children and young people: an e-cohort study.

BACKGROUND: Concerns relating to increased use of psychotropic medication contrast with those of under-treatment and under-recognition of common mental disorders in children and young people (CYP) across developed countries. Little is known about the indications recorded for antidepressant prescribing in primary care in CYP. METHOD: This was an electronic cohort study of routinely collected primary-care data from a population of 1.9 million, Wales, UK. Poisson regression was undertaken to model adjusted counts of recorded depression symptoms, diagnoses and antidepressant prescriptions. Associated indications were explored. RESULTS: 3 58 383 registered patients aged 6-18 years between 1 January 2003 and 31 December 2013 provided a total of 19 20 338 person-years of follow-up. The adjusted incidence of antidepressant prescribing increased significantly [incidence rate ratio (IRR) for 2013 = 1.28], mainly in older adolescents. The majority of new antidepressant prescriptions were for citalopram. Recorded depression diagnoses showed a steady decline (IRR = 0.72) while depression symptoms (IRR = 2.41) increased. Just over half of new antidepressant prescriptions were associated with depression (diagnosis or symptoms). Other antidepressant prescribing, largely unlicensed, was associated with diagnoses such as anxiety and pain. CONCLUSION: Antidepressant prescribing is increasing in CYP while recorded depression diagnoses decline. Unlicensed citalopram prescribing occurs outside current guidelines, despite its known toxicity in overdose. Unlicensed antidepressant prescribing is associated with a wide range of diagnoses, and while accepted practice, is often not supported by safety and efficacy studies. New strategies to implement current guidance for the management of depression in CYP are required.

Trends in suicidal ideation in England: the national psychiatric morbidity surveys of 2000 and 2007.

BACKGROUND: Recent falls in suicide rates should be accompanied by a decline in the prevalence of suicidal ideation. METHOD: We used a pseudo-cohort analytic strategy to examine trends in suicidal ideation measured identically in 2000 and 2007, in nationally representative English probability samples of adults aged ≥ 16 years. Suicidal ideation included tiredness of life, death wishes and thoughts of suicide. Logistic regression models were fitted to estimate trends in age-specific prevalence of suicidal ideation in the past year and past week between 2000 and 2007. RESULTS: There were 6799 participants aged 16-71 years in 2000, and 6815 participants aged 16-78 years in 2007. There was little evidence of trends in prevalence of suicidal ideation, with the exception of women aged 44-50 years in 2007, whose prevalence was unusually high. Prevalence of suicidal ideation in the past year followed a W-shaped profile with age, with peaks at the transition to adulthood, in the forties, and in the oldest participants. CONCLUSIONS: Despite falling suicide rates, suicidal ideation did not decline overall between 2000 and 2007. This may indicate the success of the National Suicide Prevention Strategy. Women aged 44-50 years in 2007 were, however, particularly prone to suicidal ideation. As they also have the highest age-adjusted prevalence of common mental disorders and the highest female suicide rate, there are clear implications for treatment access, availability and delivery in primary care.

Personal debt and suicidal ideation.

BACKGROUND: Personal debt is one of many factors associated with anxiety, depression and suicidality. The aim of this study was to examine the relationship between personal debt and suicidal ideation in the context of sociodemographic factors, employment and income, lifestyle behaviours, and recently experienced traumatic events. METHOD: Interviews were conducted with a random probability sample comprising 7461 respondents for the third national survey of psychiatric morbidity of adults in England. Fieldwork was carried out throughout 2007. The prevalence of suicidal thoughts in the past week, past year and lifetime was assessed and current sources of debt were recorded. RESULTS: In 2007, 4.3% of adults in England had thought about taking their own life in the past 12 months, ranging from 1.8% of men aged ≥ 55 years to 7.0% of women aged 35-54 years. Those in debt were twice as likely to think about suicide after controlling for sociodemographic, economic, social and lifestyle factors. Difficulty in making hire purchase or mail order repayments and paying off credit card debt, in addition to housing-related debt (rent and mortgage arrears), was strongly associated with suicidal thoughts. Feelings of hopelessness partially mediated the relationship between debt and suicidal ideation. CONCLUSIONS: The number of debts, source of the debt and reasons for debt are key correlates of suicidal ideation. Individuals experiencing difficulties in repaying their debts because they are unemployed or have had a relationship breakdown or have heavy caring responsibilities may require psychiatric evaluation in addition to debt counselling.

Solution structure of kistrin, a potent platelet aggregation inhibitor and GP IIb-IIIa antagonist.

The structure of kistrin, which is a member of a homologous family of glycoprotein IIb-IIIa (GP IIb-IIIa) antagonists and potent protein inhibitors of platelet aggregation, has been determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy. The 68-residue protein consists of a series of tightly packed loops held together by six disulfide bonds and has almost no regular secondary structure. Kistrin has an Arg-Gly-Asp (RGD) adhesion site recognition sequence important for binding to GP IIb-IIIa that is located at the apex of a long loop across the surface of the protein.

Do acute diffusion- and perfusion-weighted MRI lesions identify final infarct volume in ischemic stroke?

BACKGROUND AND PURPOSE: An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the "tissue-at-risk." It is unclear which "semiquantitative" perfusion parameter most closely identifies final infarct volume. METHODS: Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. "Semiquantitative" mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired > or =1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume. RESULTS: Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient rho=0.68), intermediate for CBFsq (rho=0.55), and weakest for MTTsq (rho=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch. CONCLUSIONS: Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. "DWI/PWI mismatch" does not identify lesion growth. Patients without "DWI/PWI mismatch" are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.

Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial.

BACKGROUND: Undernutrition is common in patients admitted with stroke. We aimed to establish whether the timing and route of enteral tube feeding after stroke affected patients' outcomes at 6 months. METHODS: The FOOD trials consist of three pragmatic multicentre randomised controlled trials, two of which included dysphagic stroke patients. In one trial, patients enrolled within 7 days of admission were randomly allocated to early enteral tube feeding or no tube feeding for more than 7 days (early versus avoid). In the other, patients were allocated percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding. The primary outcome was death or poor outcome at 6 months. Analysis was by intention to treat. FINDINGS: Between Nov 1, 1996, and July 31, 2003, 859 patients were enrolled by 83 hospitals in 15 countries into the early versus avoid trial. Early tube feeding was associated with an absolute reduction in risk of death of 5.8% (95% CI -0.8 to 12.5, p=0.09) and a reduction in death or poor outcome of 1.2% (-4.2 to 6.6, p=0.7). In the PEG versus nasogastric tube trial, 321 patients were enrolled by 47 hospitals in 11 countries. PEG feeding was associated with an absolute increase in risk of death of 1.0% (-10.0 to 11.9, p=0.9) and an increased risk of death or poor outcome of 7.8% (0.0 to 15.5, p=0.05). INTERPRETATION: Early tube feeding might reduce case fatality, but at the expense of increasing the proportion surviving with poor outcome. Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients.

Routine oral nutritional supplementation for stroke patients in hospital (FOOD): a multicentre randomised controlled trial.

BACKGROUND: Undernutrition is common in hospital patients with stroke, can develop or worsen in hospital, and is associated with poor outcomes. We aimed to establish whether routine oral nutritional supplements improve outcome after stroke. METHODS: The FOOD trials are a family of three pragmatic, multicentre, randomised controlled trials. We measured the outcomes of stroke patients who could swallow and who were randomly allocated normal hospital diet or normal hospital diet plus oral nutritional supplements until hospital discharge. The primary outcome was death or poor outcome (modified Rankin scale [MRS] grade 3-5), 6 months after enrollment, measured unaware of treatment allocation. Analysis was by intention to treat. FINDINGS: Between Nov 1, 1996, and July 31, 2003, 4023 patients were enrolled by 125 hospitals in 15 countries. Only 314 (8%) patients were judged to be undernourished at baseline. Vital status and MRS at the end of the trial were known for 4012 and 4004 patients, respectively. Supplemented diet was associated with an absolute reduction in risk of death of 0.7% (95% CI -1.4 to 2.7) and an increased risk of death or poor outcome of 0.7% (-2.3 to 3.8). INTERPRETATION: We could not confirm the anticipated 4% absolute benefit for death or poor outcome from routine oral nutritional supplements for mainly well nourished stroke patients in hospital. Our results would be compatible with a 1% or 2% absolute benefit or harm from oral supplements. These results do not support a policy of routine oral supplementation after stroke.

No evidence that severity of stroke in internal carotid occlusion is related to collateral arteries.

BACKGROUND/AIM: The neurological effects of internal carotid artery (ICA) occlusion vary between patients. The authors investigated whether the severity of symptoms in a large group of patients with ipsilateral or/and contralateral ICA occlusion at presentation with ocular or cerebral ischaemic symptoms could be explained by patency of other extra or intracranial arteries to act as collateral pathways. METHODS: The authors prospectively identified all patients (n = 2881) with stroke, cerebral transient ischaemic attack (TIA), retinal artery occlusion (RAO), and amaurosis fugax (AFx) presenting to our hospital over five years, obtained detailed history and examination, and examined the intra and extracranial arteries with carotid and colour-power transcranial Doppler ultrasound. For this analysis, all those with intracranial haemorrhage on brain imaging and cerebral events without brain imaging were excluded. RESULTS: Among 2228/2397 patients with brain imaging (1713 ischaemic strokes, 401 cerebral TIAs, 193 AFx, and 90 RAO) who underwent carotid Doppler, 195 (9%) had ICA occlusion. Among those patients with cortical events, disease in potential collateral arteries (contralateral ICA, external carotid, ipsilateral or contralateral vertebral or intracranial arteries) was equally distributed among patients with severe and mild ischaemic presenting symptoms. CONCLUSION: The authors found no evidence that the clinical presentation associated with an ICA occlusion was related to patency of other extra or intracranial arteries to act as collateral pathways. Further work is required to investigate what determines the clinical effects of ICA occlusion.

Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure.

BACKGROUND: Sleep-disordered breathing (SDB) is common after stroke, but it is unclear whether it should be treated. OBJECTIVE: To conduct a randomised controlled trial of continuous positive airway pressure (CPAP) after stroke. METHODS: Patients with stroke with > or = 30 apnoeas and hypopnoeas per hour ((A+H)/h) with predominant obstructive sleep apnoea or hypopnoea were randomised to either CPAP treatment or conservative treatment for 8 weeks. Outcomes were measured blind to treatment allocation at 8 weeks and 6 months after the stroke. The primary outcome was physical function on the Nottingham Extended Activities of Daily Living Scale. RESULTS: Of 658 patients with stroke screened, only 71 (10.7%) were eligible and consented to a sleep study 14-19 days after stroke. 66 patients completed the sleep study (21 women; mean age 72 years), 33 (50%) had > or = 30 (A+H)/h that were predominantly obstructive. 15 were randomised to CPAP treatment and 15 to conventional treatment. Despite intensive efforts, objective use of CPAP was poor, averaging 1.4 h a night. CPAP treatment resulted in no significant improvements (p>0.1) in the primary outcome or in neurological function or sleepiness, and in poorer health status on some measures. CONCLUSIONS: This trial showed no benefit from CPAP treatment, the relevance of the observed detrimental effects is questionable. Even in our highly selected patients with stroke, use of CPAP was poor. At present, CPAP treatment should be advocated for patients with stroke only if they have symptoms of SDB.

The factor VII zymogen structure reveals reregistration of beta strands during activation.

BACKGROUND: Coagulation factor VIIa (FVIIa) contains a Trypsin-like serine protease domain and initiates the cascade of proteolytic events leading to Thrombin activation and blood clot formation. Vascular injury allows formation of the complex between circulating FVIIa and its cell surface bound obligate cofactor, Tissue Factor (TF). Circulating FVIIa is nominally activated but retains zymogen-like character and requires TF in order to complete the zymogen-to-enzyme transition. The manner in which TF exerts this effect is unclear. The structure of TF/FVIIa is known. Knowledge of the zymogen structure is helpful for understanding the activation transition in this system. RESULTS: The 2 A resolution crystal structure of a zymogen form of FVII comprising the EGF2 and protease domains is revealed in a complex with the exosite binding inhibitory peptide A-183 and a vacant active site. The activation domain, which includes the N terminus, differs in ways beyond those that are expected for zymogens in the Trypsin family. There are large differences in the TF binding region. An unprecedented 3 residue shift in registration between beta strands B2 and A2 in the C-terminal beta barrel and hydrogen bonds involving Glu154 provide new insight into conformational changes accompanying zymogen activation, TF binding, and enzymatic competence. CONCLUSIONS: TF-mediated allosteric control of the activity of FVIIa can be rationalized. The reregistering beta strand connects the TF binding region and the N-terminal region. The zymogen registration allows H bonds that prevent the N terminus from attaining a key salt bridge with the active site. TF binding may influence an equilibrium by selecting the enzymatically competent registration.