Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

An assessment of psychological distress and professional burnout in mental health professionals in Australia during the COVID-19 pandemic.

OBJECTIVE: To examine psychological distress and professional burnout in a cohort of Australian mental healthcare workers during the COVID-19 pandemic. METHODS: This study examined a multi-disciplinary cohort of mental healthcare workers in a large metropolitan service in Australia. Demographic information as well as information on employment and individual's personal experience of the COVID-19 pandemic was collected and correlated with cross-sectional assessments of anxiety, depression and professional burnout using validated clinical questionnaires. RESULTS: Mental healthcare workers reported high levels of anxiety, depression, and professional burnout. Participants reported some reduction in anxiety since the early phases of the pandemic, but the reduction was more modest in mental healthcare workers identifying as being "vulnerable" employees. CONCLUSION: Despite the low numbers of COVID-19 cases, mental healthcare workers in Australia report significant levels of psychological distress and professional burnout during the pandemic.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

James Lind Alliance research priorities: what role do carbohydrates, fats and proteins have in the management of Type 2 diabetes, and are there risks and benefits associated with particular approaches?

AIMS: To assess the role played by carbohydrates, fat and proteins in the management of Type 2 diabetes. BACKGROUND: Diabetes research tends to reflect the interests of academics or the pharmaceutical industry, rather than those of people living with Type 2 diabetes. The James Lind Alliance and Diabetes UK addressed this issue by defining the research priorities of people living with Type 2 diabetes. Three of the top 10 research priority questions focused on lifestyle. METHODS: A narrative review was undertaken with a structured search strategy using three databases. Search terms included the three macronutrients and Type 2 diabetes. No restrictions were placed on macronutrient quantity or length of study follow-up. Outcomes included changes in HbA1c , body weight, insulin sensitivity and cardiovascular risk. RESULTS: There is no strong evidence that there is an optimal ratio of macronutrients for improving glycaemic control or reducing cardiovascular risk. Challenges included defining the independent effect of macronutrient manipulation and identifying the effects of macronutrients, independent of foods and dietary patterns. Extreme intakes of macronutrients may be associated with health risks. CONCLUSIONS: It is challenging to formulate food-based guidelines from studies based on macronutrient manipulation. Structured education should be offered to support individuals in discovering their optimal, individual dietary approach. Recommendations for dietary guidelines should be expressed in terms of foods and not macronutrients.

Carbohydrate restriction for glycaemic control in Type 2 diabetes: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to evaluate the effect of carbohydrate restriction on glycaemic control in Type 2 diabetes. METHODS: We searched Medline, EMBASE and CINAHL for the period between 1976 and April 2018. We included randomized controlled trials comparing carbohydrate restriction with a control diet which aimed to maintain or increase carbohydrate intake, and that reported HbA1c as an outcome and reported the amount of carbohydrate consumed during or at the end of the study, with outcomes reported at ≥3 months. RESULTS: We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome. Definitions of low carbohydrate varied among the studies. The pooled effect estimate from meta-analysis was a weighted mean difference of -0.09% [95% CI -0.27, 0.08 (P = 0.30); I2 72% (P <0.001)], suggesting no effect on HbA1c of restricting the quantity of carbohydrate. A subgroup analysis of diets containing 50-130 g carbohydrate resulted in a pooled effect estimate of -0.49% [95% CI -0.75, -0.23 (P <0.001); I2 0% (P = 0.56)], suggesting a clinically and statistically significant effect on HbA1c in favour of low-carbohydrate diets in studies of ≤6 months' duration. CONCLUSIONS: There was no overall pooled effect on HbA1c in favour of restricting carbohydrate; however, restriction of carbohydrate to 50-130 g per day had beneficial effects on HbA1c in trials up to 6 months. Future randomized controlled trials should be of >12 months' duration, assess pre-study carbohydrate intake, use recognized definitions of low-carbohydrate diets and examine reasons for non-adherence to prescribed diets in greater detail.

Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes.

A summary of the latest evidence-based nutrition guidelines for the prevention and management of diabetes is presented. These guidelines are based on existing recommendations last published in 2011, and were formulated by an expert panel of specialist dietitians after a literature review of recent evidence. Recommendations have been made in terms of foods rather than nutrients wherever possible. Guidelines for education and care delivery, prevention of Type 2 diabetes, glycaemic control for Type 1 and Type 2 diabetes, cardiovascular disease risk management, management of diabetes-related complications, other considerations including comorbidities, nutrition support, pregnancy and lactation, eating disorders, micronutrients, food supplements, functional foods, commercial diabetic foods and nutritive and non-nutritive sweeteners are included. The sections on pregnancy and prevention of Type 2 diabetes have been enlarged and the weight management section modified to include considerations of remission of Type 2 diabetes. A section evaluating detailed considerations in ethnic minorities has been included as a new topic. The guidelines were graded using adapted 'GRADE' methodology and, where strong evidence was lacking, grading was not allocated. These 2018 guidelines emphasize a flexible, individualized approach to diabetes management and weight loss and highlight the emerging evidence for remission of Type 2 diabetes. The full guideline document is available at www.diabetes.org.uk/nutrition-guidelines.

Dietitians' practice in giving carbohydrate advice in the management of type 2 diabetes: a mixed methods study.

BACKGROUND: Carbohydrate is accepted as the principal nutrient affecting blood glucose in diabetes; however, current guidelines are unable to specify the optimal quantity of carbohydrate for glycaemic control. No studies exist that describe current practice amongst healthcare professionals giving carbohydrate advice in type 2 diabetes. The present study aims to improve understanding of the degree of variation in the current practice of UK registered dietitians (RDs) by describing how RDs advise patients. METHODS: UK RDs were contacted through national networks and asked to complete an online survey, which was analysed using stata, version 12 (StataCorp, College Station, TX, USA). Three consultations between dietitians and patients with type 2 diabetes were observed, followed by semi-structured interviews with the dietitians. RESULTS: In total, 320 complete survey responses were received. Dietitians' advice varied according to expertise, training and confidence, and the complexity of the patient's blood glucose treatment. Some 48% (n = 154) of respondents advised patients to restrict carbohydrate intake either occasionally or frequently, with 35.6% (n = 114) considering 30-39% of total energy from carbohydrate to be a realistic expectation. The overall theme from the interviews was 'Conflicting Priorities', with three sub-themes: (i) how treatment decisions are made; (ii) the difference between empowerment and advice; and (iii) contradictory advice. A disparity existed between what was observed and interview data on how dietitians rationalise the type of carbohydrate advice provided. CONCLUSIONS: Dietitians' advice varies for a number of reasons. Consensus exists in some areas (e.g. carbohydrate awareness advice); however, clear definitions of such terms are lacking. Clarification of interventions may improve the consistency of approach and improve patient outcomes.

The impact of clozapine on hospital use: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness. METHOD: PubMed, EMBASE, PsycINFO and the Cochrane Schizophrenia Group Trials Register were systematically searched from inception to 12 October 2016. We included all trials and observational studies, except case reports. RESULTS: Thirty-seven studies were included. Clozapine significantly reduced the proportion of people hospitalised compared to control medicines (RR = 0.74; 95% CI: 0.69-0.80, P < 0.001, 22 studies, n = 44 718). There were significantly fewer bed days after clozapine treatment compared to before clozapine treatment in both controlled (MD = -34.41 days; 95% CI: -68.22 to -0.60 days, P = 0.046, n = 162) and uncontrolled studies (MD = -52.86 days; 95% CI: -79.86 days to -25.86 days, P < 0.001, n = 2917). Clozapine and control medicines had a similar time to rehospitalisation (-19.90 days; 95% CI: -62.42 to 22.63 days, P = 0.36). CONCLUSION: Clozapine treatment reduced the number of people hospitalised and the number of bed days after treatment compared with before treatment. Clozapine has the potential to reduce acute hospital use among people with treatment refractory schizophrenia.

Synthesis, X-ray crystal structures and thermal analyses of some new antimicrobial zinc complexes: New configurations and nano-size structures.

Some new five coordinated ZnLX2 complexes, where L is N3-Schiff base ligand obtained by condensation reaction between diethylenetriamine and (E)-3-(2-nitrophenyl)acrylaldehyde and X (Cl(-), Br(-), I(-), N3(-) and NCS(-)), were synthesized and characterized by FT-IR, (1)H and (13)CNMR, UV-visible, ESI-mass spectra and molar conductivity measurements. The structures of zinc iodide and thiocyanate complexes were determined by X-ray crystallographic analysis. The X-ray results showed that the Zn (II) center in these complexes is five-coordinated in a distorted trigonal-bipyramidal configuration. Zinc iodide and thiocyanate complexes crystallize in the monoclinic and triclinic systems with space groups of C2/c and P1- with eight and two molecules per unit cell respectively. The crystal packing of the complexes consists of intermolecular interactions such as C-H(…)O and C-H(…)I, C-H(···)S, N(…)O, together with π-π stacking and some other unexpected interactions. The mentioned interactions cause three-dimensional supramolecular structure in the solid state. Zinc complexes were also prepared in nano-structure by sonochemical method confirmed by XRD, SEM and TEM analyses. Moreover, ZnO nanoparticles were synthesized by direct thermolysis of zinc iodide complex. Furthermore, antimicrobial and thermal properties of the compounds were completely investigated.

Nano structure zinc (II) Schiff base complexes of a N3-tridentate ligand as new biological active agents: spectral, thermal behaviors and crystal structure of zinc azide complex.

In this work, synthesis of some new five coordinated zinc halide/pseudo-halide complexes of a N3-tridentate ligand is presented. All complexes were subjected to spectroscopic and physical methods such as FT-IR, UV-visible, (1)H and (13)C NMR spectra, thermal analyses and conductivity measurements for identification. Based on spectral data, the general formula of ZnLX2 (X=Cl(-), Br(-), I(-), SCN(-) and N3(-)) was proposed for the zinc complexes. Zinc complexes have been also prepared in nano-structure sizes under ultrasonic irradiation. X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were applied for confirmation of nano-structure character for the complexes. Among the complexes, zinc azide complex structure was analyzed by X-ray crystallography. This complex crystallizes as a triplet in trigonal system with space group of P31. The coordination sphere around the zinc center is well shown as a distorted trigonal bipyramidal with three nitrogen atoms from Schiff base ligand and two terminal azide nitrogen atoms attached to zinc ion. Various intermolecular interactions such as NH⋯N, CH⋯N and CH⋯π hydrogen bonding interactions stabilize crystalline lattice so that they causes a three dimensional supramolecular structure for the complex. In vitro screening of the compounds for their antimicrobial activities showed that ZnLI2, ZnL(N3)2, ZnLCl2 and ZnL(NCS)2 were found as the most effective compound against bacteria of Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli respectively. Also ZnLI2 and ZnLCl2 complexes were found more effective against two selected fungi than others. Finally, thermal behaviors of the zinc complexes showed that they are decomposed via 2-4 thermal steps from room temperature up to 1000°C.

The accuracy of magnetic resonance imaging in radical prostatectomy.

AIMS: The aim of this study was to examine the accuracy of standard magnetic resonance imaging (MRI) in the localised staging of prostate cancer in those who had undergone radical prostatectomy. PATIENTS AND METHODS: The cohort consisted of 110 patients who had undergone MRI for staging of prostate cancer and subsequently underwent radical prostatectomy. T stage was analysed both on MRI and from the specimen following radical surgery. RESULTS: Of the patients 57% of patients had their disease up-staged following radical surgery from preoperative MRI findings. Of those patients who had their disease up-staged following surgery, nearly 50% of patients had gone from organ confined disease at time of MRI to extra-prostatic involvement from the surgical specimen. CONCLUSION: We have reported that MRI has a wide range of accuracy. Given developments in MRI technologies further work should be pursued to help in the staging of this disease for which decision to treat is difficult.

Expression and prognostic significance of Src family members in renal clear cell carcinoma.

BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.

Prospective study of the role of inflammation in renal cancer.

BACKGROUND: The local and systemic inflammatory responses provide prognostic information in cancer. The modified Glasgow Prognostic Score (mGPS) provides additional prognostic information than C-reactive protein (CRP) alone when assessing the systemic inflammation in cancer. The aim of this study was to determine the role of local and systemic inflammation in renal cancer. METHODS: The cohort consisted of 79 patients who had undergone potential curative resection. Systemic inflammation, mGPS, was constructed by measuring preoperative CRP and albumin concentrations and the Klintrup-Makinen score was evaluated histologically for the local inflammatory response. Pathological parameters such as T stage, grade and tumour necrosis were also assessed. The local inflammatory response was assessed by examining all inflammatory cells at the tumour edge on diagnostic haematoxylin and eosin slides. RESULTS: On univariate analysis, T stage (p < 0.001), grade (p = 0.044) and mGPS (p < 0.001) were significant predictors of cancer-specific survival. On multivariate analysis, mGPS (hazard ratio 8.64, 95% confidence interval 3.5-21.29, p < 0.001) was the only significant independent predictor of cancer-specific survival. CONCLUSION: A preoperative systemic inflammatory response as measured by the mGPS is an independent predictor of poor cancer-specific survival in renal cancer in patients undergoing potential curative resection.

The interrelationships between Src, Cav-1 and RhoGD12 in transitional cell carcinoma of the bladder.

BACKGROUND: The aim of this current study was to assess the expression and activity of Src family kinases, focal adhesion kinase (FAK), caveolin (Cav-1) and RhoGD12 in bladder cancer. METHODS: Fifty-eight patients with a new diagnosis of bladder cancer undergoing transurethral resection were included. Immunohistochemical staining was utilised to assess expression of c-Src, dephosphorylated (SrcY(530)), phosphorylated Src (Y(419)), phosphorylated FAK (FAK Y(861)), Cav-1 and RhoGD12. Expression was assessed using the weighted histoscore method. RESULTS: High expression of dephosphorylated Y(527), phosphorylated Y(416) and phosphorylated FAK Y(861) in the membrane were associated with increased cancer-specific survival (P=0. 01, P=0.001, P=0.008, respectively) and expression of Y(416) in the membrane was an independent factor on multivariate analysis when combined with known clinical parameters (P=0.008, HR 0.288, 95% CI 0.11-0.72). CONCLUSION: These results demonstrate that in contrast to other solid tumours, activation of the Src family members and downstream signalling proteins are associated with a good prognosis in transitional cell carcinoma of the bladder, and activated Src has a positive relationship with RhoGD12.

Is the presence or absence of tumour necrosis a significant predictor of survival in renal cell cancer?

OBJECTIVE: Currently when renal cancer pathology is assessed the presence or absence of necrosis is simply reported. It has been suggested that a presence or absence response ignores heterogeneity and a classification based on the extent of necrosis involvement would aid prognostic value in cancer-specific survival. The aim of this study was to determine whether a quantitative assessment of tumour necrosis would provide additional prognostic information. METHODS: We studied the pathological features and cancer-specific survival of 47 patients with renal cancer undergoing surgery with curative intent. A quantitative assessment of tumour necrosis was compared to the presence or absence of necrosis. RESULTS: Tumour necrosis was present in 27 of 47 cases. A simple assessment of the presence or absence was not associated with cancer-specific survival (p = 0.052). When assessed quantitatively, tumour necrosis was associated with decreased cancer-specific survival (p < 0.001). A 2-tiered assessment, <25% and >25% involvement of necrosis, was further utilised and shown to predict cancer-specific survival (p < 0.001). On multivariate analysis, using this 2-tiered assessment of <25% and >25% involvement of necrosis was retained as a significant independent factor for cancer-specific survival (HR 11.84, 95% CI 3.81-36.75, p < 0.001). CONCLUSION: A simple assessment of the presence/absence of tumour necrosis is reported to be a prognostic factor in renal cell cancer. In this study, the presence/absence was not shown to be a significant prognostic marker of cancer-specific survival. However, a more accurate quantitative assessment of tumour necrosis, whereby a 2-tiered response is still utilised, but basing this on <25% and >25% involvement of necrosis was statistically significant and independent in predicting cancer-specific survival.

Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes.

This article summarizes the Diabetes UK evidence-based guidelines for the prevention of Type 2 diabetes and nutritional management of diabetes. It describes the development of the recommendations and highlights the key changes from previous guidelines. The nutrition guidelines include a series of recommendations for the prevention of Type 2 diabetes, nutritional management of Type 1 and Type 2 diabetes, weight management, management of microvascular and macrovascular disease, hypoglycaemia management, and additional considerations such as nutrition support, end-of-life care, disorders of the pancreas, care of the older person with diabetes, nutrition provided by external agencies and fasting. The evidence-based recommendations were graded using the Scottish Intercollegiate Guidelines Network methodology and, in a small number of topic areas, where strong evidence was lacking, the recommendations were reached by consensus. The Diabetes UK 2011 guidelines place an emphasis on carbohydrate management and a more flexible approach to weight loss, unlike previous guidelines which were expressed in terms of recommendations for individual nutrient intakes. Additionally, the guidelines for alcohol have been aligned to national recommendations. The full evidence-based nutrition guidelines for the prevention and management of diabetes are available from: http://www.diabetes.org.uk/nutrition-guidelines.

Centralised urban stormwater harvesting for potable reuse.

Urban impervious areas provide a guaranteed source of runoff, especially in cities with high rainfall - this represents a source of water with low sensitivity to unfavourable climate change. Whilst the potential to reuse stormwater has long been recognised, its quality has largely limited usage to non-potable applications requiring the use of a third-pipe network, a prohibitively expensive option in established urban areas. Given recent advances in membrane filtration, this study investigates the potential of harvesting and treating stormwater to a potable standard to enable use of the potable distribution network. A case study based on the Throsby Creek catchment in Newcastle explores the issue. The high seasonally uniform rainfall provides insight into the maximum potential of such an option. Multicriterion optimisation was used to identify Pareto optimal solutions for harvesting, storing and treating stormwater. It is shown that harvesting and treating stormwater from a 13 km² catchment can produce yields ranging from 8.5 to 14.2 ML/day at costs ranging from AU$2.60/kL to AU$2.89/kL, which may become viable as the cost of traditional supply continues to grow. However, there are significant social impacts to deal with including alienation of public land for storage and community acceptance of treated stormwater.

Improper adjustment for baseline in genetic association studies of change in phenotype.

OBJECTIVE: In studies of associations between genetic factors and outcomes where change in phenotype is of interest, proper modeling of the data, particularly the treatment of baseline trait values, is required to draw valid conclusions. METHODS: The authors compared models of blood pressure response to a cold pressor test with and without inclusion of baseline blood pressure as a regressor and evaluate the resultant biases. RESULTS: Adjustment for baseline presents a potential source of bias for assessment of genotype-phenotype associations. This bias was observed to occur both under the absence of a true effect, as well when a relation between genotype and change in phenotype was simulated. In simulations that incorporated measurement error, estimates were as great as two fold the true parameter values when unmeasured confounding was a factor. CONCLUSIONS: Adjusting for baseline introduces bias in genetic association studies when change in phenotype is the outcome of interest. Model misspecification bias may impact inference and provide one possible source of non-replication of findings in the literature.

Alcohol abuse in adolescents.

Alcohol abuse by adolescents is widespread in the United Kingdom, has complex cultural, economic and biological origins and is associated with adverse health consequences. Affected young people present medically with intoxication or its immediate consequences such as injury or self-harm. A significant number also suffer adverse psychosocial effects and longer-term adverse outcomes. Even some younger patients are now presenting with evidence of physiological dependence. Interpretation of the literature and clinical experience suggests that practitioners have greater capacity to respond effectively than they may believe. Modest concerted effort could make the medical profession much more relevant to the needs of these, often troubled, young people.