bluuebunny/crossref_metadata_2025 huggingface dataset:
Major complications of epidural anesthesia: a prospective study of 5083 cases at a single hospital
Authors: KANG X.‐H. , BAO F.‐P. , XIONG X.‐X. , LI M. , JIN T.‐T. , SHAO J. , ZHU S.‐M.
Published: June 2014

Background

We undertook a prospective study of non‐obstetric epidurals placed in surgical inpatients at a single teaching hospital to evaluate the incidence of and potential risk factors for major complications of continuous epidural anesthesia.

Methods

Demographic information, details of the epidural procedure, and complications (from the pre‐anesthetic period through resolution) were recorded for more than 5000 surgical inpatients who underwent continuous epidural anesthesia in our institution between March 2009 and April 2011. The incidence of and risk factors for major complications were evaluated.

Results

During the study period, 5083 patients were interviewed and their details were recorded (98% capture rate). Sixty‐nine (1.36%) experienced major complications: epidural hematoma in 1 patient (0.02%), post‐operative neurologic deficits in 57 patients (1.12%), post‐dural puncture headache in 7 patients (0.14%), and systemic local anesthetic toxicity in 4 patients (0.08%). Only one patient had permanent sequelae: unilateral lower limb paresthesia. Identified risk factors for neurologic deficits were as follows: American Society of Anesthesiologists status II–III, siting in the lumbar region, orthopedic and urologic surgery, multiple attempts to site an epidural, paresthesia during insertion, a history of neuraxial anesthesia, and use of patient‐controlled epidural analgesia.

Conclusions

Serious complications were very rare; only one patient had permanent sequelae, and a single epidural hematoma was diagnosed. Post‐operative neurologic deficits were more common, but most complications resolved spontaneously within 3 months and they rarely required intervention.
Neurofunctional changes in adolescent cannabis users with and without bipolar disorder
Authors: Bitter Samantha M. , Adler Caleb M. , Eliassen James C. , Weber Wade A. , Welge Jeffrey A. , Burciaga Joaquin , Shear Paula K. , Strakowski Stephen M. , DelBello Melissa P.
Published: June 2014

Aims

To compare regional brain activation among adolescents with bipolar disorder and co‐occurring cannabis use disorder.

Design

Cross‐sectional study.

Setting

Cincinnati, OH, USA.

Participants

Adolescents with bipolar disorder (BP, n = 14), adolescents with cannabis use disorder (MJ, n = 13), adolescents with co‐occurring cannabis use and bipolar disorders (BPMJ, n = 25) and healthy adolescents (HC, n = 15).

Measurements

Cannabis craving, substance use, Blood Oxygenation Level Dependent (BOLD) signal assessed by the Marijuana Craving Questionnaire (MCQ), Teen‐Addiction Severity Index (T‐ASI) and a cannabis cue–reactivity task during a functional magnetic resonance imaging (fMRI) session, respectively.

Findings

The BP group exhibited significantly greater brain activation than the BPMJ group in the right amygdala (F = 4.14, P = 0.046), left nucleus accumbens (F = 3.8, P = 0.02), left thalamus (F = 3.8, P < 0.05) and the right thalamus (F = 6.2, P = 0.02). The BP group exhibited significantly greater activation than the HC group in the left nucleus accumbens (F = 11.5, P = 0.0001), right thalamus (F = 4.9, P = 0.03) and the left striatum (F = 3.6, P = 0.04). Left amygdala activation of the BPMJ group trended towards being significantly negatively correlated with the number of joints smoked (R = −0.4, P = 0.06).

Conclusions

Bipolar adolescents with comorbid cannabis use do not exhibit the same over‐activation of the regions involved in emotional processing as seen in adolescents with bipolar disorder alone. The absence of these findings in patients with comorbid bipolar and cannabis use disorders suggests that these individuals may have a unique endophenotype of bipolar disorder or that cannabis use may alter brain activation uniquely in bipolar disorder patients who use cannabis.
Efficacy of brief motivational interviewing on smoking cessation at tuberculosis clinics in Tshwane, South Africa: a randomized controlled trial
Authors: Louwagie Goedele M. C. , Okuyemi Kolawole S. , Ayo‐Yusuf Olalekan A.
Published: June 2014

Background and Aims

Tuberculosis (TB) patients who smoke risk adverse TB outcomes and other long‐term health effects of smoking. This study aimed to determine the efficacy of brief motivational interviewing by lay health‐care workers (LHCWs) in assisting TB patients to quit smoking.

Design

Multi‐centre two‐group parallel individual randomized controlled trial.

Setting

Six primary care tuberculosis clinics in a South African township.

Participants

Newly diagnosed adult TB patients identified as current smokers were randomized to brief motivational interviewing by a LHCW (intervention group, n = 205) or brief smoking cessation advice from a TB nurse (control group, n = 204).

Measurements

The primary outcome was self‐reported sustained 6‐month smoking abstinence. Exhaled carbon monoxide (CO) testing was offered to about half the participants. Secondary outcomes were sustained abstinence at 3 months; 7‐day point prevalence abstinence at 1, 3 and 6 months; and quit attempts. Allocation was concealed. Primary analysis relied on intention to treat. Multi‐level analysis accounted for site heterogeneity of effect.

Findings

Self‐reported 6‐month sustained abstinence was 21.5% for the intervention group versus 9.3% for the control group [relative risk (RR) = 2.29, 95% confidence interval (CI) = 1.34, 3.92]. Biochemically verified 6‐month sustained abstinence was also higher in the intervention group (RR 2.21, 95% CI = 1.08, 4.51) for the 166 participants who were offered carbon monoxide testing. Self‐reported 3‐month sustained abstinence was 25.4% for the intervention group and 12.8% for the control group (RR = 1.98, 95% CI = 1.24, 3.18).

Conclusions

Motivational interviewing by lay counsellors to promote smoking cessation in tuberculosis patients in South Africa approximately doubled sustained smoking abstinence for at least 6 months compared with brief advice alone.
Flowcytometric diagnosis of atracurium‐induced anaphylaxis
Authors: Uyttebroek A. P. , Sabato V. , Leysen J. , Bridts C. H. , De Clerck L. S. , Ebo D. G.
Published: June 2014

Background

Allergy to atracurium is a rare condition with serious consequences of diagnostic error. However, correct diagnosis is not always straightforward. The aim of this study is to assess the utility of the basophil activation test (BAT) in atracurium sensitization and to investigate its role in identifying cross‐reactivity between muscle relaxants.

Methods

For validation, eight patients with perioperative anaphylaxis to atracurium and seven individuals experiencing perioperative anaphylaxis but not exposed to neuromuscular blocking agents (NMBA) were included. Furthermore, five other patient groups were included in the study, and all individuals exposed to different NMBA, either sensitized or not to the drug. Basophil activation with atracurium was analysed flow cytometrically.

Results

ROC analyses between eight atracurium‐sensitized patients and seven nonexposed controls allowed identification of 5% as the decision threshold for BAT positivity. For this cutoff, the BAT attained a sensitivity of 63%, specificity of 100%, positive predictive value of 100% and negative predictive value of 70%. Of the atracurium‐exposed individuals with a negative atracurium skin test (ST), two individuals had a clear positive BAT. BAT atracurium was positive in one cisatracurium‐sensitized patient and negative in all cisatracurium‐exposed patients with a negative ST to cisatracurium. All rocuronium‐ and suxamethonium‐sensitized patients displayed a negative BAT with atracurium.

Conclusions

The BAT proves to be a useful diagnostic for atracurium‐induced anaphylaxis and may be complementary to STs. The technique enables quick and simultaneous testing of potentially crossreactive NMBA and the identification of safe alternatives for future surgery.
Effect of socioeconomic position on patient outcome after hysterectomy
Authors: Daugbjerg Signe B. , Cesaroni Giulia , Ottesen Bent , Diderichsen Finn , Osler Merete
Published: June 2014

Objective

To investigate the association between socioeconomic position (assessed by education, employment and income) and complications following hysterectomy and assess the role of lifestyle, co‐morbidity and clinical conditions on the relationship.

Design

Register‐based cohort study.

Setting and population

The study included nearly all Danish women (n = 22 150) registered with a benign elective hysterectomy in the Danish Hysterectomy Database in 2004–2008.

Methods

Data were analyzed using logistic regression models estimating the odds ratio with 95% confidence intervals.

Main outcome measures

Complications following hysterectomy.

Results

Seventeen percent of the women experienced complications in relation to the hysterectomy. Women with less than high school education and unemployed women had higher odds of infection, complications and readmission than women with more than high school education and employed women. Furthermore, unemployed women had higher odds of hospitalization >4 days than women in employment. Lifestyle factors (smoking and body mass index) and co‐morbidity status seemed to explain most of the social differences. However, an association between women with less than high school education and all complications remained unexplained. Furthermore, differences in lifestyle and co‐morbidity status only partially explained the higher odds of infection, complications and hospitalization >4 days for unemployed than employed women.

Conclusion

Women with a low socioeconomic position have significantly higher odds of complications following hysterectomy compared with women with a high socioeconomic position. Unhealthy lifestyle and presence of co‐morbidity in women with low socioeconomic position partially explains the differences in complications.
Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects
Authors: Sidharta Patricia N. , van Giersbergen Paul L. M. , Wolzt Michael , Dingemanse Jasper
Published: June 2014

Aim

To study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects.

Methods

In this open‐label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of macitentan and its active metabolite ACT‐132577 (treatments A and C) and sildenafil and its N‐desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non‐compartmentally.

Results

The pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT‐132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N‐desmethylsildenafil were not affected by macitentan. All treatments were well tolerated.

Conclusion

A minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.
The impact of co‐administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers
Authors: Liu Yong , Zhou Simon , Wan Yuntao , Wu Anfan , Palmisano Maria
Published: June 2014

Aims

Two clinical studies were conducted to determine possible drug−drug interactions between apremilast and a strong CYP3A4 inhibitor, ketoconazole, or a potent CYP3A4 inducer, rifampicin. The main objectives of these two studies were to evaluate the impact of multiple doses of ketoconazole on the pharmacokinetics of apremilast and its metabolites, and the effect of multiple oral doses of rifampicin on the pharmacokinetics of apremilast.

Methods

These single centre, open label, sequential treatment studies in healthy subjects included two treatment periods for ketoconazole and three treatment periods for rifampicin. Apremilast was administered as a 20 mg (ketoconazole study) or 30 mg (rifampicin study) single oral dose.

Results

Ketoconazole increases overall exposure (AUC(0,∞)) of apremilast by ≈36% (2827 vs. 2072 ng ml−1 h, 90% CI = 126.2, 147.5) and peak exposure (Cmax) by 5% (247 vs. 236 ng ml−1). Multiple doses of rifampicin increase apremilast clearance ≈3.6‐fold and decrease apremilast mean AUC(0,∞) by ≈72% (3120 vs. 869 ng ml−1 h, 90% CI = 25.7, 30.4) and Cmax (from 290 vs. 166 ng ml−1) relative to that of apremilast given alone. A 30 min intravenous infusion of rifampicin 600 mg had negligible effects on the overall exposure (AUC(0,∞)) of apremilast (2980 vs. 3120 ng ml−1 h, 90% CI = 88.0, 104.1).

Conclusion

Ketoconazole slightly decreased apremilast clearance, resulting in a small increase in AUC which is probably not meaningful clinically. However, the effect of CYP3A4 induction by rifampicin on apremilast clearance is much more pronounced than that of CYP3A4 inhibition by ketoconazole. Strong CYP3A4 inducers may result in a loss of efficacy of apremilast because of decreased drug exposure.
Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5‐fluorouracil: a meta‐analysis of published trials
Authors: Iacovelli Roberto , Pietrantonio Filippo , Palazzo Antonella , Maggi Claudia , Ricchini Francesca , de Braud Filippo , Di Bartolomeo Maria
Published: June 2014

Aim

Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5‐fluorouracil (5‐FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5‐FU in randomized clinical trials (RCTs).

Methods

MEDLINE and Cochrane Library were reviewed for RCTs that compared capecitabine with 5‐FU for treatment of solid malignancies. The incidence and relative risk (RR) of grade 3/4 diarrhoea were estimated for each arm in the overall population and in colorectal cancer (CRC) patients

Results

Twenty‐three studies and 15 761 patients were included. Among these 8303 and 7458 patients received capecitabine or 5‐FU based therapies, respectively. In the overall populations severe diarrhoea was reported in 16.6% (95% CI 15.8, 17.4) and in 12.7% (95% CI 11.9, 13.4) of patients treated with capecitabine or 5‐FU‐based therapies, respectively. The RR was 1.39 (95% CI 1.14, 1.69, P = 0.0010). In 14 899 CRC patients, the incidence of severe diarrhoea was 17.0% (95% CI 16.2, 17.9) and 12.9% (95% CI 12.1, 13.7), respectively, with a RR of 1.46 (95% CI 1.18, 1.81, P < 0.0001). In CRC patients treated with combined chemotherapy, the RR was 1.40 (95% CI 1.07, 1.82; P = 0.01) for patients receiving oxaliplatin and 2.35 (95% CI 1.76, 3.13; P < 0.0001) for patients receiving irinotecan.

Conclusions

Treatment with capecitabine is characterized by an increased risk of severe diarrhoea, mainly in patients affected by CRC and treated with polichemotherapy. Combination treatment with irinotecan doubles the risk over 5‐FU.
Covariate selection in pharmacometric analyses: a review of methods
Authors: Hutmacher Matthew M. , Kowalski Kenneth G.
Published: June 2014

Covariate selection is an activity routinely performed during pharmacometric analysis. Many are familiar with the stepwise procedures, but perhaps not as many are familiar with some of the issues associated with such methods. Recently, attention has focused on selection procedures that do not suffer from these issues and maintain good predictive properties. In this review, we endeavour to put the main variable selection procedures into a framework that facilitates comparison. We highlight some issues that are unique to pharmacometric analyses and provide some thoughts and strategies for pharmacometricians to consider when planning future analyses.
Effect of pregnancy on the course of immune thrombocytopenia: a retrospective study of 118 pregnancies in 82 women
Authors: Loustau Valentine , Debouverie Odile , Canoui‐Poitrine Florence , Baili Lilia , Khellaf Mehdi , Touboul Claudine , Languille Laetitia , Loustau Marine , Bierling Philippe , Haddad Bassam , Godeau Bertrand , Pourrat Olivier , Michel Marc
Published: June 2014

In women with pre‐existing immune thrombocytopenic purpura (ITP), the effect of pregnancy on the course of the disease is poorly known. We performed a dual‐centre retrospective cohort study of 118 pregnancies in 82 women with primary ITP. In early pregnancy, the platelet count was <100 × 109/l in 35·6% of pregnancies. During pregnancy the median platelet count nadir was 66 × 109/l (25th–75th percentile: 42–117), with platelet count <30 × 109/l for 26 pregnancies (22%). In 49% of pregnancies, a significant decrease of the platelet count required treatment at least transiently in preparation for delivery. At the time of delivery, the median platelet count was 110 × 109/l (77–155). Compared to before pregnancy, at 3 months post‐partum, only 11% of pregnancies [95% confidence interval (95% CI): 6·8–20·2] showed disease worsening. Previous splenectomy was the only factor significantly associated with ITP worsening after pregnancy (53·9% vs. 10·3%, P < 0·001). For 8·3% of the pregnancies (95% CI: 3·8–15·1), neonatal thrombocytopenia required treatment, especially in case of previous maternal splenectomy (adjusted odds ratio 16·7, 95% CI: 2·61–106). The overall risk of exacerbation of ITP and severe thrombocytopenia during pregnancy is acceptable.
Long‐term follow‐up of a multicentre randomised controlled trial comparing tension‐free vaginal tape, xenograft and autologous fascial slings for the treatment of stress urinary incontinence in women
Authors: Khan Zainab A. , Nambiar Arjun , Morley Roland , Chapple Christopher R. , Emery Simon J. , Lucas Malcolm G.
Published: June 2014

Objective

To compare the long‐term outcomes of a tension‐free vaginal tape (TVT; Gynecare™, Somerville, NJ, USA), autologous fascial sling (AFS) and xenograft sling (porcine dermis, Pelvicol™; Bard, Murray Hill, NJ, USA) in the management of female stress urinary incontinence (SUI).

Patients and Methods

A multicentre randomised controlled trial carried out in four UK centres from 2001 to 2006 involving 201 women requiring primary surgery for SUI. The women were randomly assigned to receive TVT, AFS or Pelvicol. The primary outcome was surgical success defined as ‘women reporting being completely ‘dry’ or ‘improved’ at the time of follow‐up’. The secondary outcomes included ‘completely dry’ rates, changes in the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) and EuroQoL EQ‐5D questionnaire scores.

Results

In all, 162 (80.6%) women were available for follow‐up with a median (range) duration of 10 (6.6–12.6) years. ‘Success’ rates for TVT, AFS and Pelvicol were 73%, 75.4% and 58%, respectively. Comparing the 1‐ and 10‐year ‘success’ rates, there was deterioration from 93% to 73% (P < 0.05) in the TVT arm and 90% to 75.4% (P < 0.05) in the AFS arm; ‘dry’ rates were 31.7%, 50.8% and 15.7%, respectively. Overall, the ‘dry’ rates favoured AFS when compared with Pelvicol (P < 0.001) and TVT (P = 0.036). The re‐operation rate for persistent SUI was 3.2% (two patients) in the TVT arm, 13.1% (five) in the Pelvicol arm, while none of the patients in the AFS arm required further intervention.

Conclusions

Our study indicates there is not enough evidence to suggest a difference in long‐term success rates between AFS and TVT. However, there is some evidence that ‘dry’ rates for AFS may be more durable than TVT.
Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II‐induced hypertensive heart disease in rats
Authors: Snijder P M , Frenay A R , de Boer R A , Pasch A , Hillebrands J L , Leuvenink H G D , van Goor H
Published: June 2014

Background and Purpose

Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)‐induced hypertensive cardiac disease in rats.

Experimental Approach

Male Sprague Dawley rats were infused with Ang II (435 ng kg min−1) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl).

Key Results

Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased.

Conclusions and Implications

Ang II‐induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐6
A Guide to Understanding Social Science Research for Natural Scientists
Authors: MOON KATIE , BLACKMAN DEBORAH
Published: June 2014

Natural scientists are increasingly interested in social research because they recognize that conservation problems are commonly social problems. Interpreting social research, however, requires at least a basic understanding of the philosophical principles and theoretical assumptions of the discipline, which are embedded in the design of social research. Natural scientists who engage in social science but are unfamiliar with these principles and assumptions can misinterpret their results. We developed a guide to assist natural scientists in understanding the philosophical basis of social science to support the meaningful interpretation of social research outcomes. The 3 fundamental elements of research are ontology, what exists in the human world that researchers can acquire knowledge about; epistemology, how knowledge is created; and philosophical perspective, the philosophical orientation of the researcher that guides her or his action. Many elements of the guide also apply to the natural sciences. Natural scientists can use the guide to assist them in interpreting social science research to determine how the ontological position of the researcher can influence the nature of the research; how the epistemological position can be used to support the legitimacy of different types of knowledge; and how philosophical perspective can shape the researcher's choice of methods and affect interpretation, communication, and application of results. The use of this guide can also support and promote the effective integration of the natural and social sciences to generate more insightful and relevant conservation research outcomes.

Una Guía para Entender la Investigación de Ciencias Sociales para las Ciencias Naturales Katie Moon
Non‐Bayesian Noun Generalization in 3‐ to 5‐Year‐Old Children: Probing the Role of Prior Knowledge in the Suspicious Coincidence Effect
Authors: Jenkins Gavin W. , Samuelson Larissa K. , Smith Jodi R. , Spencer John P.
Published: June 2014

It is unclear how children learn labels for multiple overlapping categories such as “Labrador,” “dog,” and “animal.” Xu and Tenenbaum (2007a) suggested that learners infer correct meanings with the help of Bayesian inference. They instantiated these claims in a Bayesian model, which they tested with preschoolers and adults. Here, we report data testing a developmental prediction of the Bayesian model—that more knowledge should lead to narrower category inferences when presented with multiple subordinate exemplars. Two experiments did not support this prediction. Children with more category knowledge showed broader generalization when presented with multiple subordinate exemplars, compared to less knowledgeable children and adults. This implies a U‐shaped developmental trend. The Bayesian model was not able to account for these data, even with inputs that reflected the similarity judgments of children. We discuss implications for the Bayesian model, including a combined Bayesian/morphological knowledge account that could explain the demonstrated U‐shaped trend.
Constrained Labour Agency and the Changing Regulatory Regime in China
Authors: Chan Chris King‐Chi
Published: June 2014

Using the concept of ‘constrained agency’ introduced by Neil Coe and David Jordhus‐Lier, this article attempts to evaluate the possibilities and constraints facing labour agency in the Pearl River Delta in China. By reviewing the social, economic and political background of the changing labour market and labour regulations in China, and through an intensive case study of a workers’ strike and its consequences, the author argues that Chinese migrant workers have begun to challenge the state's regulatory regime on labour, which is based on individual rights. However, the introduction of a regulatory framework based on collective rights is being impeded by the party‐state's manipulation of trade unions and the strong influence of global capital on local labour policy.
Modulation of insulin dose titration using a hypoglycaemia‐sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin‐naïve people with type 2 diabetes
Authors: Home P. D. , Bolli G. B. , Mathieu C. , Deerochanawong C. , Landgraf W. , Candelas C. , Pilorget V. , Dain M.‐P. , Riddle M. C.
Published: June 2014

Aims

To examine whether insulin glargine can lead to better control of glycated haemoglobin (HbA1c) than that achieved by neutral protamine Hagedorn (NPH) insulin, using a protocol designed to limit nocturnal hypoglycaemia.

Methods

The present study, the Least One Oral Antidiabetic Drug Treatment (LANCELOT) Study, was a 36‐week, randomized, open‐label, parallel‐arm study conducted in Europe, Asia, the Middle East and South America. Participants were randomized (1 : 1) to begin glargine or NPH, on background of metformin with glimepiride. Weekly insulin titration aimed to achieve median prebreakfast and nocturnal plasma glucose levels ≤5.5 mmol/l, while limiting values ≤4.4 mmol/l.

Results

The efficacy population (n = 701) had a mean age of 57 years, a mean body mass index of 29.8 kg/m2, a mean duration of diabetes of 9.2 years and a mean HbA1c level of 8.2% (66 mmol/mol). At treatment end, HbA1c values and the proportion of participants with HbA1c <7.0 % (<53 mmol/mol) were not significantly different for glargine [7.1 % (54 mmol/mol) and 50.3%] versus NPH [7.2 % (55 mmol/mol) and 44.3%]. The rate of symptomatic nocturnal hypoglycaemia, confirmed by plasma glucose ≤3.9 or ≤3.1 mmol/l, was 29 and 48% less with glargine than with NPH insulin. Other outcomes were similar between the groups.

Conclusion

Insulin glargine was not superior to NPH insulin in improving glycaemic control. The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins. This study confirms, in a globally heterogeneous population, the reduction achieved in nocturnal hypoglycaemia while attaining good glycaemic control with insulin glargine compared with NPH, even when titrating basal insulin to prevent nocturnal hypoglycaemia rather than treating according to normal fasting glucose levels.
Economic evaluations of interventions designed to prevent mental disorders: a systematic review
Authors: Mihalopoulos Cathrine , Chatterton Mary Lou
Published: June 2014

Aim

The prevention of mental disorders is a growing field and there are interventions that have been demonstrated to prevent some disorders, particularly depression, from developing. The aim of the current study is to update two existing reviews of the cost‐effectiveness studies of preventive interventions for mental disorders in order to determine whether such interventions are good value‐for‐money.

Methods

A search was undertaken in Medline, PsycInfo and Econlit. The search was limited to articles published in English covering the period from 2010 to September 2013. Inclusion criteria for the review comprised comparative economic evaluations of interventions designed to prevent mental disorders.

Results

Ten new economic evaluations have been published since 2010, more than doubling the numbers of economic evaluations of preventive interventions for mental disorders published prior to 2010. Using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, the majority of studies were of a good standard and used cost‐utility frameworks.

Conclusions

Indicated types of interventions for the prevention of depression and anxiety appeared to be particularly good value‐for‐money and most of these studies were modelled evaluations. Unfortunately, many such interventions are still not routinely provided. Future trials of preventive interventions for mental disorders need to include robust economic evaluations so that the economic impact of such interventions from the individual study participant perspective can be determined.
Screening for psychotic experiences: social desirability biases in a non‐clinical sample
Authors: DeVylder Jordan E. , Hilimire Matthew R.
Published: June 2014

Aim

Subthreshold psychotic experiences are common in the population and may be clinically significant. Reporting of psychotic experiences through self‐report screens may be subject to threats to validity, including social desirability biases. This study examines the influence of social desirability on the reporting of psychotic experiences.

Methods

College students (n = 686) completed a psychosis screen and the Marlowe–Crowne social desirability scale as part of a self‐report survey battery. Associations between psychosis and social desirability were tested using logistic regression models.

Results

With the exception of auditory hallucinations, all other measures of psychotic experiences were subject to social desirability biases. Respondents who gave more socially desirable answers were less likely to report psychotic experiences.

Conclusions

Respondent's tendency to underreport psychotic experiences should be accounted for when screening for these symptoms clinically. Findings also suggest that population figures based on self‐report may underestimate the prevalence of subthreshold delusions but not hallucinations.
Attitudes towards cannabis use and genetic testing for schizophrenia
Authors: Schiffman Jason , Lawrence Ryan E. , Demro Caroline , Appelbaum Paul S. , Dixon Lisa B.
Published: June 2014

Aim

Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests.

Methods

We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use.

Results

Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use.

Conclusions

Results suggest that cannabis users and non‐users were positively influenced in terms of intentions to change behaviour based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people's attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia.
‘Nobody really gets it’: a qualitative exploration of youth mental health in deprived urban areas
Authors: Schaffalitzky Elisabeth , Leahy Dorothy , Armstrong Claire , Gavin Blanaid , Latham Linda , McNicholas Fiona , Meagher David , O'Connor Ray , O'Toole Thomas , Smyth Bobby P. , Cullen Walter
Published: June 2014

Aim

To examine the experience of developing and living with mental health and substance use disorders among young people living in urban‐deprived areas in Ireland to inform primary care interventions.

Method

Semi‐structured qualitative interviews with 20 young adults attending health and social care agencies in two deprived urban areas, and analysed using thematic analysis.

Results

Five themes were identified: experiencing symptoms, symptom progression, delay accessing help, loss of control/crisis point, and consequences of mental health and substance use disorders. As young people delayed help, symptoms disrupted normal life progression and they found themselves unable to engage in everyday activities, and living with reduced potential. Living in deprived areas influenced the development of problems: many had added stressors, less familial support and early exposure to violence, addiction and bereavement.

Conclusion

Young people in urban‐deprived areas are especially vulnerable to mental health and substance use disorders. Early identification in primary care appears necessary in halting symptom and illness progression, improving young people's chances of achieving their potential.
Methods for individualising factor VIII dosing in prophylaxis
Authors: Ar Muhlis Cem , Vaide Ines , Berntorp Erik , Björkman Sven
Published: June 2014

Haemophilia A is a sex‐linked disorder characterised chiefly by recurrent, spontaneous joint and muscle bleedings resulting from deficiency of factor VIII (FVIII). Recurrent joint bleeds result in haemophilic arthropathy. Unless treated with factor replacement therapy, many patients with severe haemophilia become disabled. The first clinical evidence favouring prophylaxis originated from the studies in Sweden and the Netherlands in the 1960s. Later on, it was shown that prophylaxis could prevent arthropathy, if started early in life, or slow its progression in adults with established arthropathy. The optimal dosing of FVIII in long‐term prophylaxis has still not been determined, and there is growing evidence that the dose and frequency of FVIII should be individualised. We conducted a systematic search of PubMed to identify all relevant articles on FVIII prophylaxis in severe haemophilia A. We focused on articles with detailed information about individualisation of prophylaxis. Long‐term prophylaxis in haemophilia was introduced in Sweden in the late 1950s. However, standard prophylactic regimens may not be appropriate for all patients with severe haemophilia. Factors such as age, joint status, co‐morbidities and differences in pharmacokinetics lead to interindividual variation in factor requirement. Dose tailoring of FVIII by clinical outcome was first described in 1994. Since then, several dose‐finding studies questioned the necessity to maintain preinfusion levels of FVIII above 1%. Individualising prophylaxis by dose tailoring is now recommended. Each country should adopt policies for individualising prophylaxis in patients with severe haemophilia. This would lead to a better distribution of the available source of factor concentrates.
Assay discrepancy in mild haemophilia A
Authors: Armstrong Elina , Hillarp Andreas
Published: June 2014

There are three main methods used to assay factor VIII (FVIII) activity: the one‐stage and two‐stage clotting assays and the two‐stage chromogenic method. The most commonly used assay for the diagnosis of haemophilia A is the automated one‐stage FVIII assay. The classical two‐stage FVIII assays are less frequently used. The chromogenic FVIII:C assay is a variant of the two‐stage assay. It is easier to use and therefore used more commonly. Recently significant assay discrepancy has been recognised in the FVIII:C measurements in approximately one‐third of mild haemophilia A patients. This so‐called discrepant mild haemophilia A is characterised by a high ratio of one‐stage/two‐stage assay with one‐stage FVIII levels that are typically more than double those of the two‐stage coagulation assay. There are several mutations that destabilise the FVIIIa structure that can explain this result of a more pronounced decrease of the chromogenic FVIII:C activity compared with the one‐stage activity. These mutations are clustered at the interfaces of the A1, A2 and A3 domains of the FVIII protein. The inverse discrepancy, where the one‐stage assay gives lower FVIII:C results than the chromogenic assay, seems to be associated with mutations found close to important sites for thrombin cleavage or FIX binding. We are carrying out a study of mild haemophilia A samples from the Malmö Haemophilia Centre of families with a unique F8 genotype. The activity of FVIII will be measured using a chromogenic assay and two different one‐stage assays. We hope to estimate the true size of assay discrepancy.

Aim

This project will review assay discrepancy in mild/moderate haemophilia A and the risk of misdiagnosis. The overall aim is to estimate the size of the problem and to learn from the literature and experiences from our centre as well as to suggest recommendations on how to avoid misdiagnosis.
Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy
Authors: Citraro Rita , Chimirri Serafina , Aiello Rossana , Gallelli Luca , Trimboli Francesca , Britti Domenico , De Sarro Giovambattista , Russo Emilio
Published: June 2014

Objective

Statins (3‐hydroxy‐3‐methylglutaryl‐coenzyme A [HMG‐CoA] reductase inhibitors) exert cholesterol‐independent pleiotropic effects that include antithrombotic, antiinflammatory, and antioxidative properties. Moreover, both in vitro and in vivo studies have shown neuroprotective, antiseizure, and antiexcitotoxic effects of statins, suggesting their potential role in the treatment of neurologic diseases. Only a few studies have investigated whether statins modulate absence seizure activity and epileptogenesis.

Methods

We investigated the effects of atorvastatin (5 and 10 mg/kg/day), simvastatin (10 mg/kg/day), and pravastatin (10 and 30 mg/kg/day), given orally for 17 consecutive weeks (starting at 45 days of age), on the development of absence seizures (electroencephalography [EEG] recordings), depressive‐like behavior (forced swimming test [FST]), and anxiety levels (open field test [OF]) in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij) rats at the age of 6 months (1 month after suspension). WAG/Rij rats are a genetic animal model of absence epilepsy, epileptogenesis, and mild‐depression comorbidity. The effects of statins were also studied after acute intraperitoneal injection for 4 h after administration of various doses in 6‐months‐old rats. Plasma cholesterol levels were measured throughout drug treatment.

Results

We found that early long‐term statin treatment possesses antiepileptogenic properties, reduced immobility time in the FST, and reduced anxiety in the OF, whereas they were not effective against established absence seizures when acutely administered. The observed effects were not related to changes in plasma cholesterol levels, which remained unchanged during drug treatment.

Significance

Our results suggest that statins administration might be a possible intervention and promising strategy for preventing the epileptogenesis and/or behavioral comorbidity.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Adjunctive use of controlled‐release pregabalin in adults with treatment‐resistant partial seizures: A double‐blind, randomized, placebo‐controlled trial
Authors: French Jacqueline , Brandt Christian , Friedman Daniel , Biton Victor , Knapp Lloyd , Pitman Verne , Chew Marci , Dubrava Sarah , Posner Holly B.
Published: June 2014

Objectives

To assess the efficacy and tolerability of add‐on pregabalin controlled‐release formulation (PGB‐CR) (doses of 165 or 330 mg/day) in patients with partial‐onset seizures (POS).

Methods

This was a randomized, double‐blind (DB), parallel‐group study of PGB‐CR once‐daily as adjunctive treatment in adults with treatment‐resistant partial seizures. After an 8‐week baseline period, eligible patients were randomized (1:1:1) to placebo, PGB‐CR 165 mg, or PGB‐CR 330 mg for 14 weeks, including a 2‐week dose escalation. Primary endpoint was the loge‐transformed 28‐day seizure rate for all POS with observable component during the full 14‐week double‐blind treatment phase. Secondary endpoints included the 50% responder rate and percent change from baseline in 28‐day POS rate.

Results

Three hundred twenty‐three patients were randomized and received treatment; placebo (n = 110), PGB‐CR 330 mg (n = 100), PGB‐CR 165 mg (n = 113); and 287 (88.9%) completed the trial. The primary efficacy analysis result, expressed as percent reduction from placebo, was 13.1% and 1.0% for PGB‐CR 330 mg and PGB‐CR 165 mg, respectively, and was not statistically significant (p = 0.091, 0.908). The proportion of 50% responders was similar for placebo (35.8%) and 165 mg PGB‐CR (37.8%) and nominally higher for 330 mg PGB‐CR (45.9%, p = 0.125 compared to placebo). The LS mean estimates of the percent change from baseline for placebo (−5.7%) was nominally smaller than 165 mg PGB‐CR (−15.0%, p = 0.540) and 330 mg PGB‐CR (−31.5%, p = 0.079); however, the median percent changes from baseline were not as well differentiated (placebo, −35.4%; 165 mg PGB‐CR, −38.0%; 330 mg PGB‐CR −43.4%). Rates of adverse events (AEs) were low for placebo and study drug; the most frequent reported AEs were dizziness, somnolence, and fatigue, consistent with the immediate‐release formulation.

Significance

Results from this trial did not demonstrate that PGB‐CR is effective in reducing seizure frequency below that of placebo. Both doses of PGB‐CR were shown to be safe and well‐tolerated.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Memory impairment is not necessarily related to seizure frequency in mesial temporal lobe epilepsy with hippocampal sclerosis
Authors: Pacagnella Denise , Lopes Tatila M. , Morita Marcia E. , Yasuda Clarissa L. , Cappabianco Fabio A. M. , Bergo Felipe , Balthazar Marcio L. F. , Coan Ana C. , Cendes Fernando
Published: June 2014

Objective

To investigate the effect of seizure frequency on memory, we performed a cross sectional study comparing mesial temporal lobe epilepsy (MTLE) patients with frequent and infrequent seizures.

Methods

We performed magnetic resonance imaging (MRI) hippocampal volume (HV) measurements and neuropsychological assessment in 22 patients with frequent seizures (at least one dyscognitive seizure [DS] per month) that were refractory to antiepileptic drugs and 20 patients with infrequent seizures (three or less DS per year and no event evolving to a bilateral convulsive seizure), all with MRI signs of hippocampal sclerosis (HS) on visual analysis. We also included 29 controls for comparison of volumetric data.

Results

There was no difference in memory performance between patients with frequent seizures and infrequent seizures. We observed a significant bilateral reduction of HV in patients with MTLE when compared to controls (p < 0.001). The degree of hippocampal atrophy (HA) between patients with frequent and infrequent seizures was not different. There was a negative correlation between seizure frequency and HV, with r = −0.3 for the HV ipsilateral to the HS and r = −0.55 for the contralateral side, thus, explaining only 9% and 30% of the HV loss. There was a positive correlation between age of onset and degree of HA (r = 0.37).

Significance

Our data suggest that seizure frequency does not explain most of the HV loss or memory impairment in MTLE. Memory impairment appears to be more influenced by hippocampal damage than by seizure frequency. Further studies are necessary to identify the factors that influence memory decline in patients with MTLE.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
A field guide to whole‐genome sequencing, assembly and annotation
Authors: Ekblom Robert , Wolf Jochen B. W.
Published: June 2014

Genome sequencing projects were long confined to biomedical model organisms and required the concerted effort of large consortia. Rapid progress in high‐throughput sequencing technology and the simultaneous development of bioinformatic tools have democratized the field. It is now within reach for individual research groups in the eco‐evolutionary and conservation community to generate de novo draft genome sequences for any organism of choice. Because of the cost and considerable effort involved in such an endeavour, the important first step is to thoroughly consider whether a genome sequence is necessary for addressing the biological question at hand. Once this decision is taken, a genome project requires careful planning with respect to the organism involved and the intended quality of the genome draft. Here, we briefly review the state of the art within this field and provide a step‐by‐step introduction to the workflow involved in genome sequencing, assembly and annotation with particular reference to large and complex genomes. This tutorial is targeted at scientists with a background in conservation genetics, but more generally, provides useful practical guidance for researchers engaging in whole‐genome sequencing projects.