Region Zealand

BACKGROUND: The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well-being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. METHODS: We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. RESULTS: A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. CONCLUSIONS: The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields.

CONTEXT: Morbidity and mortality rates in patients with eating disorders are thought to be high, but exact rates remain to be clarified. OBJECTIVE: To systematically compile and analyze the mortality rates in individuals with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). DATA SOURCES: A systematic literature search, appraisal, and meta-analysis were conducted of the MEDLINE/PubMed, PsycINFO, and Embase databases and 4 full-text collections (ie, ScienceDirect, Ingenta Select, Ovid, and Wiley-Blackwell Interscience). STUDY SELECTION: English-language, peer-reviewed articles published between January 1, 1966, and September 30, 2010, that reported mortality rates in patients with eating disorders. DATA EXTRACTION: Primary data were extracted as raw numbers or confidence intervals and corrected for years of observation and sample size (ie, person-years of observation). Weighted proportion meta-analysis was used to adjust for study size using the DerSimonian-Laird model to allow for heterogeneity inclusion in the analysis. DATA SYNTHESIS: From 143 potentially relevant articles, we found 36 quantitative studies with sufficient data for extraction. The studies reported outcomes of AN during 166 642 person-years, BN during 32 798 person-years, and EDNOS during 22 644 person-years. The weighted mortality rates (ie, deaths per 1000 person-years) were 5.1 for AN, 1.7 for BN, and 3.3 for EDNOS. The standardized mortality ratios were 5.86 for AN, 1.93 for BN, and 1.92 for EDNOS. One in 5 individuals with AN who died had committed suicide. CONCLUSIONS: Individuals with eating disorders have significantly elevated mortality rates, with the highest rates occurring in those with AN. The mortality rates for BN and EDNOS are similar. The study found age at assessment to be a significant predictor of mortality for patients with AN. Further research is needed to identify predictors of mortality in patients with BN and EDNOS.

The aim of the present study was to focus on the relative contributions of personality, psychological health and cognitive coping to post-traumatic growth in patients with recent myocardial infarction (MI). The sample consisted of 139 patients who had experienced a first-time acute MI between 3 and 12 months before data assessment. Multivariate relationships were tested by means of Structural Equation Modeling. The results showed that besides the contribution of personality and psychological health, a significant amount of variance in growth was explained by the cognitive coping strategies people used to handle their MI. As cognitive coping strategies are generally assumed to be mechanisms that are subject to potential influence and change, this provides us with important targets for intervention.

OBJECTIVE: The purpose of this review was to examine the literature assessing the relationship between prenatal exposure to nicotine, alcohol, caffeine, and psychosocial stress during pregnancy to the risk of developing behavioral problems related to attention deficit hyperactivity disorder (ADHD) in childhood. METHOD: PubMed, MEDLINE, EMBASE, and PsycINFO were searched systematically. Studies using DSM diagnostic criteria and other validated diagnostic or screening instruments for ADHD and those examining ADHD symptoms were included. A narrative approach was used because the studies differed too much in methods and data sources to permit a quantitative meta-analysis. RESULTS: Twenty-four studies on nicotine (tobacco smoking), nine on alcohol, one on caffeine, and five on psychosocial stress were identified. All were published between 1973 and 2002. In spite of inconsistencies, the studies on nicotine indicated a greater risk of ADHD-related disorders among children whose mothers smoked during pregnancy. Contradictory findings were reported in the alcohol studies, and no conclusion could be reached on the basis of the caffeine study. Results from studies on psychological stress during pregnancy were inconsistent but indicated a possible modest contribution to ADHD symptoms in the offspring. Many studies suffered from methodological shortcomings, such as recall bias, crude or inaccurate exposure assessments, low statistical power, and lack of or insufficient control of confounders. A general lack of information on familial psychopathology also limited the interpretations. CONCLUSIONS: Exposure to tobacco smoke in utero is suspected to be associated with ADHD and ADHD symptoms in children. Other maternal lifestyle factors during pregnancy may also be associated with these disorders. Further studies are needed to reach conclusions.

RATIONALE: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES: To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482).

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

BACKGROUND: In a European trial in 8 countries, the subjective well-being of patients on alternative forms of treatment for insulin-dependent diabetes was compared using the 28-item WHO Well-Being Questionnaire, covering four dimensions of depression, anxiety, energy and positive well-being. The objective of the analysis reported here has been to identify the items of the WHO questionnaire which belong to an overall index of negative and positive well-being. METHODS: Adult patients at 10 study centres in 8 countries who had been on insulin for at least 2 years were invited to participate in a randomised, cross-over trial to compare insulin pump treatment with injection therapy. At each phase, patients completed questions on well-being and general health. Internal validity of the well-being index was evaluated by Cronbach's alpha and Loevinger's and Mokken's homogeneity coefficients, as well as factor analysis. External validity was evaluated by comparisons with results of the general assessment questions and by the ability to discriminate between the alternative forms of treatment. RESULTS: 358 patients had sufficient data for analysis. Ten items were found to constitute a valid index of well-being with respect to internal and external validity. Coefficients of homogeneity were acceptable and there was evidence for both concurrent and discriminant validity. CONCLUSIONS: The WHO (Ten) well-being index includes negative and positive aspects of well-being in a single uni-dimensional scale. Its advantage lies in its ability to show overall change along the continuum of well-being, thus facilitating comparisons between patient groups and treatments. It is not specific to diabetes, and therefore may be useful as a disease-independent index of well-being in a broad range of health care studies.

INTRODUCTION: The International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE. AIM: The aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE. METHODS: In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted. RESULTS: The committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. CONCLUSION: The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE. Serefoglu EC, McMahon CG, Waldinger MD, Althof SE, Shindel A, Adaikan G, Becher EF, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An evidence-based unified definition of lifelong and acquired premature ejaculation: Report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. Sex Med 2014;2:41-59.

BACKGROUND: Over the decades, a variety of psychological interventions for borderline personality disorder (BPD) have been developed. This review updates and replaces an earlier review (Stoffers-Winterling 2012). OBJECTIVES: To assess the beneficial and harmful effects of psychological therapies for people with BPD. SEARCH METHODS: In March 2019, we searched CENTRAL, MEDLINE, Embase, 14 other databases and four trials registers. We contacted researchers working in the field to ask for additional data from published and unpublished trials, and handsearched relevant journals. We did not restrict the search by year of publication, language or type of publication. SELECTION CRITERIA: Randomised controlled trials comparing different psychotherapeutic interventions with treatment-as-usual (TAU; which included various kinds of psychotherapy), waiting list, no treatment or active treatments in samples of all ages, in any setting, with a formal diagnosis of BPD. The primary outcomes were BPD symptom severity, self-harm, suicide-related outcomes, and psychosocial functioning. There were 11 secondary outcomes, including individual BPD symptoms, as well as attrition and adverse effects. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials, extracted data, assessed risk of bias using Cochrane's 'Risk of bias' tool and assessed the certainty of the evidence using the GRADE approach. We performed data analysis using Review Manager 5 and quantified the statistical reliability of the data using Trial Sequential Analysis. MAIN RESULTS: We included 75 randomised controlled trials (4507 participants), predominantly involving females with mean ages ranging from 14.8 to 45.7 years. More than 16 different kinds of psychotherapy were included, mostly dialectical behaviour therapy (DBT) and mentalisation-based treatment (MBT). The comparator interventions included treatment-as-usual (TAU), waiting list, and other active treatments. Treatment duration ranged from one to 36 months. Psychotherapy versus TAU Psychotherapy reduced BPD symptom severity, compared to TAU; standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.70 to -0.33; 22 trials, 1244 participants; moderate-quality evidence. This corresponds to a mean difference (MD) of -3.6 (95% CI -4.4 to -2.08) on the Zanarini Rating Scale for BPD (range 0 to 36), a clinically relevant reduction in BPD symptom severity (minimal clinical relevant difference (MIREDIF) on this scale is -3.0 points). Psychotherapy may be more effective at reducing self-harm compared to TAU (SMD -0.32, 95% CI -0.49 to -0.14; 13 trials, 616 participants; low-quality evidence), corresponding to a MD of -0.82 (95% CI -1.25 to 0.35) on the Deliberate Self-Harm Inventory Scale (range 0 to 34). The MIREDIF of -1.25 points was not reached. Suicide-related outcomes improved compared to TAU (SMD -0.34, 95% CI -0.57 to -0.11; 13 trials, 666 participants; low-quality evidence), corresponding to a MD of -0.11 (95% CI -0.19 to -0.034) on the Suicidal Attempt Self Injury Interview. The MIREDIF of -0.17 points was not reached. Compared to TAU, psychotherapy may result in an improvement in psychosocial functioning (SMD -0.45, 95% CI -0.68 to -0.22; 22 trials, 1314 participants; low-quality evidence), corresponding to a MD of -2.8 (95% CI -4.25 to -1.38), on the Global Assessment of Functioning Scale (range 0 to 100). The MIREDIF of -4.0 points was not reached. Our additional Trial Sequential Analysis on all primary outcomes reaching significance found that the required information size was reached in all cases. A subgroup analysis comparing the different types of psychotherapy compared to TAU showed no clear evidence of a difference for BPD severity and psychosocial functioning. Psychotherapy may reduce depressive symptoms compared to TAU but the evidence is very uncertain (SMD -0.39, 95% CI -0.61 to -0.17; 22 trials, 1568 participants; very low-quality evidence), corresponding to a MD of -2.45 points on the Hamilton Depression Scale (range 0 to 50). The MIREDIF of -3.0 points was not reached. BPD-specific psychotherapy did not reduce attrition compared with TAU. Adverse effects were unclear due to too few data. Psychotherapy versus waiting list or no treatment Greater improvements in BPD symptom severity (SMD -0.49, 95% CI -0.93 to -0.05; 3 trials, 161 participants), psychosocial functioning (SMD -0.56, 95% CI -1.01 to -0.11; 5 trials, 219 participants), and depression (SMD -1.28, 95% CI -2.21 to -0.34, 6 trials, 239 participants) were observed in participants receiving psychotherapy versus waiting list or no treatment (all low-quality evidence). No evidence of a difference was found for self-harm and suicide-related outcomes. Individual treatment approaches DBT and MBT have the highest numbers of primary trials, with DBT as subject of one-third of all included trials, followed by MBT with seven RCTs. Compared to TAU, DBT was more effective at reducing BPD severity (SMD -0.60, 95% CI -1.05 to -0.14; 3 trials, 149 participants), self-harm (SMD -0.28, 95% CI -0.48 to -0.07; 7 trials, 376 participants) and improving psychosocial functioning (SMD -0.36, 95% CI -0.69 to -0.03; 6 trials, 225 participants). MBT appears to be more effective than TAU at reducing self-harm (RR 0.62, 95% CI 0.49 to 0.80; 3 trials, 252 participants), suicidality (RR 0.10, 95% CI 0.04, 0.30, 3 trials, 218 participants) and depression (SMD -0.58, 95% CI -1.22 to 0.05, 4 trials, 333 participants). All findings are based on low-quality evidence. For secondary outcomes see review text. AUTHORS' CONCLUSIONS: Our assessments showed beneficial effects on all primary outcomes in favour of BPD-tailored psychotherapy compared with TAU. However, only the outcome of BPD severity reached the MIREDIF-defined cut-off for a clinically meaningful improvement. Subgroup analyses found no evidence of a difference in effect estimates between the different types of therapies (compared to TAU) . The pooled analysis of psychotherapy versus waiting list or no treatment found significant improvement on BPD severity, psychosocial functioning and depression at end of treatment, but these findings were based on low-quality evidence, and the true magnitude of these effects is uncertain. No clear evidence of difference was found for self-harm and suicide-related outcomes. However, compared to TAU, we observed effects in favour of DBT for BPD severity, self-harm and psychosocial functioning and, for MBT, on self-harm and suicidality at end of treatment, but these were all based on low-quality evidence. Therefore, we are unsure whether these effects would alter with the addition of more data.

Importance: Prosthetic mesh is frequently used to reinforce the repair of abdominal wall incisional hernias. The benefits of mesh for reducing the risk of hernia recurrence or the long-term risks of mesh-related complications are not known. Objective: To investigate the risks of long-term recurrence and mesh-related complications following elective abdominal wall hernia repair in a population with complete follow-up. Design, Setting, and Participants: Registry-based nationwide cohort study including all elective incisional hernia repairs in Denmark from January 1, 2007, to December 31, 2010. A total of 3242 patients with incisional repair were included. Follow-up until November 1, 2014, was obtained by merging data with prospective registrations from the Danish National Patient Registry supplemented with a retrospective manual review of patient records. A 100% follow-up rate was obtained. Exposures: Hernia repair using mesh performed by either open or laparoscopic techniques vs open repair without use of mesh. Main Outcomes and Measures: Five-year risk of reoperation for recurrence and 5-year risk of all mesh-related complications requiring subsequent surgery. Results: Among the 3242 patients (mean age, 58.5 [SD, 13.5] years; 1720 women [53.1%]), 1119 underwent open mesh repair (34.5%), 366 had open nonmesh repair (11.3%), and 1757 had laparoscopic mesh repair (54.2%). The median follow-up after open mesh repair was 59 (interquartile range [IQR], 44-80) months, after nonmesh open repair was 62 (IQR, 44-79) months, and after laparoscopic mesh repair was 61 (IQR, 48-78) months. The risk of the need for repair for recurrent hernia following these initial hernia operations was lower for patients with open mesh repair (12.3% [95% CI, 10.4%-14.3%]; risk difference, -4.8% [95% CI, -9.1% to -0.5%]) and for patients with laparoscopic mesh repair (10.6% [95% CI, 9.2%-12.1%]; risk difference, -6.5% [95% CI, -10.6% to -2.4%]) compared with nonmesh repair (17.1% [95% CI, 13.2%-20.9%]). For the entirety of the follow-up duration, there was a progressively increasing number of mesh-related complications for both open and laparoscopic procedures. At 5 years of follow-up, the cumulative incidence of mesh-related complications was 5.6% (95% CI, 4.2%-6.9%) for patients who underwent open mesh hernia repair and 3.7% (95% CI, 2.8%-4.6%) for patients who underwent laparoscopic mesh repair. The long-term repair-related complication rate for patients with an initial nonmesh repair was 0.8% (open nonmesh repair vs open mesh repair: risk difference, 5.3% [95% CI, 4.4%-6.2%]; open nonmesh repair vs laparoscopic mesh repair: risk difference, 3.4% [95% CI, 2.7%-4.1%]). Conclusions and Relevance: Among patients undergoing incisional repair, sutured repair was associated with a higher risk of reoperation for recurrence over 5 years compared with open mesh and laparoscopic mesh repair. With long-term follow-up, the benefits attributable to mesh are offset in part by mesh-related complications.

BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent. OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). SECONDARY OUTCOMES: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. OBJECTIVES: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. SEARCH METHODS: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. DATA COLLECTION AND ANALYSIS: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. MAIN RESULTS: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). AUTHORS' CONCLUSIONS: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Author(s): Hopwood, Christopher J; Kotov, Roman; Krueger, Robert F; Watson, David; Widiger, Thomas A; Althoff, Robert R; Ansell, Emily B; Bach, Bo; Bagby, R Michael; Blais, Mark A; Bornovalova, Marina A; Chmielewski, Michael; Cicero, David C; Conway, Christopher; De Clercq, Barbara; De Fruyt, Filip; Docherty, Anna R; Eaton, Nicholas R; Edens, John F; Forbes, Miriam K; Forbush, Kelsie T; Hengartner, Michael P; Ivanova, Masha Y; Leising, Daniel; Livesley, W John; Lukowitsky, Mark R; Lynam, Donald R; Markon, Kristian E; Miller, Joshua D; Morey, Leslie C; Mullins‐Sweatt, Stephanie N; Ormel, J Hans; Patrick, Christopher J; Pincus, Aaron L; Ruggero, Camilo; Samuel, Douglas B; Sellbom, Martin; Slade, Tim; Tackett, Jennifer L; Thomas, Katherine M; Trull, Timothy J; Vachon, David D; Waldman, Irwin D; Waszczuk, Monika A; Waugh, Mark H; Wright, Aidan GC; Yalch, Mathew M; Zald, David H; Zimmermann, Johannes

OBJECTIVE: Early detection in first-episode psychosis confers advantages for negative, cognitive, and depressive symptoms after 1, 2, and 5 years, but longitudinal effects are unknown. The authors investigated the differences in symptoms and recovery after 10 years between regional health care sectors with and without a comprehensive program for the early detection of psychosis. METHOD: The authors evaluated 281 patients (early detection, N=141) 18 to 65 years old with a first episode of nonaffective psychosis between 1997 and 2001. Of these, 101 patients in the early-detection area and 73 patients in the usual-detection area were followed up at 10 years, and the authors compared their symptoms and recovery. RESULTS: A significantly higher percentage of early-detection patients had recovered at the 10-year follow-up relative to usual-detection patients. This held true despite more severely ill patients dropping out of the study in the usual-detection area. Except for higher levels of excitative symptoms in the early-detection area, there were no symptom differences between the groups. Early-detection recovery rates were higher largely because of higher employment rates for patients in this group. CONCLUSIONS: Early detection of first-episode psychosis appears to increase the chances of milder deficits and superior functioning. The mechanisms by which this strategy improves the long-term prognosis of psychosis remain speculative. Nevertheless, our findings over 10 years may indicate that a prognostic link exists between the timing of intervention and outcome that deserves additional study.

BACKGROUND: Mental pain, defined as a subjective experience characterized by perception of strong negative feelings and changes in the self and its function, is no less real than other types of grief. Mental pain has been considered to be a distinct entity from depression. We have performed a systematic review analyzing the relationship between mental pain and suicide by providing a qualitative data synthesis of the studies. METHODS: We have conducted, in accordance with PRISMA guidelines, a systematic search for the literature in PubMed, Web Of Science, and Scopus. Search terms were "mental pain" "OR" "psychological pain" OR "psychache" combined with the Boolean "AND" operator with "suicid*." In addition, a manual search of the literature, only including the term "psychache," was performed on Google Scholar for further studies not yet identified. RESULTS: Initial search identified 1450 citations. A total of 42 research reports met the predefined inclusion criteria and were analyzed. Mental pain was found to be a significant predictive factor of suicide risk, even in the absence of a diagnosed mental disorder. Specifically, mental pain is a stronger factor of vulnerability of suicidal ideation than depression. CONCLUSION: Mental pain is a core clinical factor for understanding suicide, both in the context of mood disorders and independently from depression. Health care professionals need to be aware of the higher suicidal risk in patients reporting mental pain. In this regard, psychological assessment should include a clinimetric evaluation of mental pain in order to further detect its contribution to suicidal tendency.

BACKGROUND: The ICD-11 classification of Personality Disorders focuses on core personality dysfunction, while allowing the practitioner to classify three levels of severity (Mild Personality Disorder, Moderate Personality Disorder, and Severe Personality Disorder) and the option of specifying one or more prominent trait domain qualifiers (Negative Affectivity, Detachment, Disinhibition, Dissociality, and Anankastia). Additionally, the practitioner is also allowed to specify a Borderline Pattern qualifier. This article presents how the ICD-11 Personality Disorder classification may be applied in clinical practice using five brief cases. CASE PRESENTATION: (1) a 29-year-old woman with Severe Personality Disorder, Borderline Pattern, and prominent traits of Negative Affectivity, Disinhibition, and Dissociality; (2) a 36-year-old man with Mild Personality Disorder, and prominent traits of Negative Affectivity and Detachment; (3) a 26-year-old man with Severe Personality Disorder, and prominent traits of Dissociality, Disinhibition, and Detachment; (4) a 19-year-old woman with Personality Difficulty, and prominent traits of Negative Affectivity and Anankastia; (5) a 53-year-old man with Moderate Personality Disorder, and prominent traits of Anankastia and Dissociality. CONCLUSIONS: The ICD-11 Personality Disorder classification was applicable to five clinical cases, which were classified according to Personaity Disorder severity and trait domain qualifiers. We propose that the classification of severity may help inform clinical prognosis and intensity of treatment, whereas the coding of trait qualifiers may help inform the focus and style of treatment. Empirical investigation of such important aspects of clinical utility are warranted.

The receptor for human urokinase-type plasminogen activator (u-PA) was purified from phorbol 12-myristate 13-acetate-stimulated U937 cells by temperature-induced phase separation of detergent extracts, followed by affinity chromatography with immobilized diisopropyl fluorophosphate-treated u-PA. The purified protein shows a single 55-60 kDa band after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining. It is a heavily glycosylated protein, the deglycosylated polypeptide chain comprising only 35 kDa. The glycosylated protein contains N-acetyl-D-glucosamine and sialic acid, but no N-acetyl-D-galactosamine. Glycosylation is responsible for substantial heterogeneity in the receptor on phorbol ester-stimulated U937 cells, and also for molecular weight variations among various cell lines. The amino acid composition and the NH2-terminal amino acid sequence are reported. The protein has a high content of cysteine residues. The NH2-terminal sequence is not closely related to any known sequence. The identification of the purified and sequenced protein with the human u-PA receptor is based on the following findings: 1) the ability of the purified protein to bind u-PA and its amino-terminal fragment; 2) the identical electrophoretic mobilities observed for cross-linked conjugates, formed between either the purified protein or the u-PA receptor on intact U937 cells and the above ligands; 3) the identity of the apparent molecular weight of the purified protein to that predicted for the u-PA receptor in the same cross-linking studies; 4) the identical extent of glycosylation of the purified protein and of the u-PA receptor in crude membrane fractions, as detected after cross-linking; 5) the ability of antibodies raised against the purified protein to inhibit cellular binding of the amino-terminal fragment of u-PA.

BACKGROUND: Nursing theories have attempted to shape the everyday practice of clinical nurses and patient care. However, many theories-because of their level of abstraction and distance from everyday caring activity-have failed to help nurses undertake the routine practical aspects of nursing care in a theoretically informed way. OBJECTIVE: The purpose of the paper is to present a point-of-care theoretical framework, called the fundamentals of care (FOC) framework, which explains, guides, and potentially predicts the quality of care nurses provide to patients, their carers, and family members. DISCUSSION: The theoretical framework is presented: person-centered fundamental care (PCFC)-the outcome for the patient and the nurse and the goal of the FOC framework are achieved through the active management of the practice process, which involves the nurse and the patient working together to integrate three core dimensions: establishing the nurse-patient relationship, integrating the FOC into the patient's care plan, and ensuring that the setting or context where care is transacted and coordinated is conducive to achieving PCFC outcomes. Each dimension has multiple elements and subelements, which require unique assessment for each nurse-patient encounter. IMPLICATIONS: The FOC framework is presented along with two scenarios to demonstrate its usefulness. The dimensions, elements, and subelements are described, and next steps in the development are articulated.

Abstract Introduction The International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE. Aim The aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE. Methods In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted. Results The committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. Conclusion The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE.