To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.
Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed.
Community-based multi-centered study based in Toronto across 5 academic sites.
Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls.
We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores.
A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD.
This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.
ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:
1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-
2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)
3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.
Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation.
To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer’s disease (AD).
Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta–gamma coupling were assessed at the same time points using the N-back task and EEG.
There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta–gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta–gamma coupling.
This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586)
OBJECTIVES/GOALS: Peri-implantitis is the inflammation of peri-implant mucosa and subsequent loss of supporting bone. Its treatment is only <40% successful mainly due to persistent bacterial infection. The goal of this project is to increase success rates by developing a robust antibiofilm multi-biomolecular membrane that can be placed around implant surfaces. METHODS/STUDY POPULATION: A collagen membrane was soaked in the antimicrobial peptide GL13K solution overnight to form an interpenetrating fibrillary network. The nanostructure of the membrane was imaged with scanning electron microscope (SEM). The hydrophobicity of the membrane was analyzed by water contact angle (WCA) measurements. The biodegradability was tested in a 0.01 mg/mL Type I collagenase solution for up to 5 weeks. The antimicrobial activity of the membrane was assessed with Gram-positive oral bacteria Streptococcus gordonii. The cytotoxicity was evaluated by culturing human gingival fibroblasts (HGF), and the osteogenesis was assessed using preosteoblasts MC3T3. Pure collagen membrane was used as the control. Statistical significance (p<0.05) was determined by one-way ANOVA with Tukey’s HSD test. RESULTS/ANTICIPATED RESULTS: The antimicrobial peptide GL13K self-assembled to short fibrils (< 1 µm long), which entangled with the larger collagen fibers (around 200 nm in diameter). The collagen fibers presented characteristic periodic banding structures, which provided biomimetic cues for cell behavior as extracellular matrix. The interpenetrated GL13K fibrils turned the highly hydrophilic collagen membrane to a hydrophobic membrane (WCA = 135 °) and significantly reduced the rate of degradation by collagenases. The developed membrane was efficient in preventing the attachment of S. gordonii. A large portion of the attached bacteria was killed on the surface of the membrane. The incorporation of GL13K did not affect the cytocompatibility of the membrane for HGF. DISCUSSION/SIGNIFICANCE OF IMPACT: We developed an antibiofilm membrane with interpenetrating collagen and antimicrobial peptide fibrils. The strong antimicrobial activity and low cytotoxicity support its further translational evaluation as scaffolds for increasing success rate in treating peri-implantitis.
Current treatment approaches for depression center on various forms of psychosocial therapy and the use of antidepressant drugs. The response rates for both of these approaches are similar, with mostly reduction, but not complete remission, of symptoms. Poor adherence to recommended treatment is an issue complicating the management of depression and prevention of recurrent episodes. This study evaluated the efficacy of a novel form of receptive music therapy which can be easily adminstered to out patients.
Enrolled subjects (n=203, average age 49.6 ± 13.1 years, 28.1% male) were randomized into four arms: Music Therapy 1 (MT1), Music Therapy 2 (MT2), Placebo (nature sounds) and waiting-list Control. Subjects listened for 30 minutes, twice daily. Multivariate linear regression models assessed depressive symptom changes over five weeks, based on a composite scale (COMP) and the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS-D) alone.
On average, a significant, positive change in COMP was observed for MT1 (β=1.44, p=0.030), but not for MT2 (β=1.14, p=0.059) or Placebo (β=0.57, p=0.397). After 15 weeks, study participation was associated with a mean HAM-D score reduction of 60% for 89,1% of the compliant probands.
Newly composed receptive music therapy, as explored in this study, is associated with reduced depressive symptoms and high treatment compliance, and may therefore potentially represent an effective depression treatment alternative or adjunctive therapy to pharmacological and psychosocial approaches.
When comparing the efficay of antipsychotics in clinical studies it would be of high practical relevance to know which doses of the respective drugs would result in equivalent blocking of dopamine-D2-receptors. This study aimed to find clinically applicable dose equivalents for haloperidol, risperidone and olanzapine.
As the occurrence of EPS correlates closely with a blockade of about 80% or more of dopamin-D2-receptors the proportion of patients developing EPS in relation to various doses of either Haloperidol (n=5252), risperidone (n=5017) or olanzapine (n =5029) was calculated. This retrospective, observational study included 20.252 inpatients from 20 hospitals with a diagnosis of schizophrenia and related disorders (ICD10 F20-25). The prescription of anticholinergic medication was utilized as surrogate parameter for the occurrence of EPS. OR, RR and NNH under different doses of AP were calculated and data entered into a probit model to predict the risk of EPS over a continuous dose range. For filtering the data ToscanaJ (FBA) was used.
1.) Same doses of risperidone and haloperidol induced the same proportion of EPS, reflected in a constant dose ratio of both drugs of ∼ 1:1 over the whole dose range.
2.) Over the whole dose range there was no linear relation between olanzapine on one hand and haloperidol and risperidone on the other hand.
3.) The results were corroborated by the probit analysis.
Previous clinical trials comparing olanzapine, risperidone and haloperidol found higher risks of EPS for Haloperidol. We propose a new model to calculate dose equivalents.
The majority of women in drug treatment facilities are of childbearing age. According to a SAMHSA Report, four percent of women aged between 15 and 44, are pregnant while entering treatment systems. These women represent a challenging patient population, that is in need of a comprehensive model of care, consisting of psychiatrists, psychologists, social workers, nurses and OBGYNs. Exposure to illegal substances during pregnancy may have consequences on the course of pregnancy and neonatal outcome. The fact that almost all patients showing up are also nicotine-dependent, should be taken into account, as neonatal withdrawal symptoms can be worsened. Furthermore, substance dependent women often find themselves in a situation of psychosocial instability. Prevalence of co-morbid somatic (e.g. hepatitis C, malnutrition) and psychiatric disorders (PTSD, depression)is high. As these pregnancies are rated as “high-risk”, prenatal checks should be undergone frequently. Recommended treatment for opioid-dependent, pregnant women is maintenance therapy with opioids. Post-delivery, 55 – 94% of infants exposed to substances in utero, may develop a neonatal abstinence syndrome (NAS). Incidence, time of onset and severity of NAS are associated with type of substances used. A standardized procedure of assessment and monitoring of NAS, as well as pharmacological and non-pharmacological treatment of these neonates is highly needed. By the means of a multi-professional treatment approach, the length of hospital stay may be shortened dramatically. In regard to a better future outcome, special aftercare (medical care plus psychosocial support) for mothers and infants should be provided, as well as further research.
Increasing research interest is focussing also on Quality of Life (QoL) in substance dependent individuals. QoL-assessments have been acknowledged as promising measurements in order to evaluate drug treatment programs.
A prospective, randomized, double-blind, double-dummy, cross-over study design was used in order to compare methadone and slow-release morphine maintenance on patients´ QoL. Sixty-four participants were randomized between two treatment groups receiving either slow-release morphine capsules for 7 weeks followed by methadone oral solution for another 7 weeks (group A), or vice versa (group B). At baseline, week 7 and week 14 QoL status was evaluated using the German version of the Lancashire Quality of Life Profile.
A significant time effect with respect to the domains: general state of health (0.018), mental health (p=0.001), general well-being (p<0.001), leisure time at home (p=0.032) and leisure time out of home (p=0.008). Our findings did not show any statistically significant differences between between the two treatment groups in any Quality of Life scores at week 7 and 14. At the end of study phase (week 14) group A showed significant increases in the domains general well-being (0.010), leisure time at home (p=0.014). Significant improvements for group B were assessed with regard to general well-being (p=0.003), mental health (p=0.003) and general state of health (p=0.017).
The development of treatment programs should focus also on the patients´ subjective perspective. According to our findings agonistic opioid maintenance treatment yields not only to treatment response but also to improvements in patients quality of life.
The effect of treatment (28 days) with zopiclone, triazolam, flunitrazepam and placebo on sleep quality and daytime well-being was proven in a randomised, double-blind, parallel group, multicentre study in private practice. Results of an exploratory statistic of treatment efficacy in a subgroup of 1,291 patients suffering from insomnia are presented. Patients met the following criteria: insomnia lasting at least four weeks and the presence of at least two of the following: 1) sleep latency ≥ 45 minutes, 2) total sleep time ≤ 6 hours, and 3) nocturnal awakening ≥3 times. Treatment efficacy was assessed according to the following factors: either a shortening of sleep latency by at least 15 minutes, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a refreshed feeling in the morning as well as no impairment in daytime well-being due to tiredness or anxiety. The total response rate was markedly higher with zopiclone (42.3%; p = 0.0003) than with placebo (29.0%). Triazolam (36.6%; p = 0.0905) and flunitrazepam (33.1%; p = 0.3401) were also more effective than the placebo, but they both tended to have a lower response rate than with zopiclone (p = 0.1199 and 0.0151, respectively). Total response was found to be essentially a reflection of the response of the socially important parameter of daytime well-being. These results suggest that zopiclone is more effective in the treatment of insomnia than either triazolam or flunitrazepam. Since the response of daytime well-being to therapy was generally poor, this parameter embodies the next main therapeutic challenge in the treatment of patients with insomnia.
Depression is a prevalent, often chronic and disabling disease. Current psychosocial and antidepressant treatments result in similar response rates with mostly symptom reduction, but not complete remission. Poor treatment adherence complicates depression management and prevention of recurrent episodes. Therefore, new therapies must be developed urgently, that alone or combined with present treatments, can significantly improve therapy outcomes.
Depression is potentially associated with decreased heart rate variability (HRV). Based on our previous studies' results which demonstrated HRV increase following auditory stimulation, we developed two interventions based on specifically for depression treatment composed and arranged music and tested the efficacy in a waiting list and placebo controlled double-blind study with depressed outpatients.
Depression status was assessed at the beginning of T1 and T2 using the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS-D) and by a composite (COMP) scale based on HAM-D, BDI and HADS-D z-scores. Changes in depressive symptoms between T1 and T2 (5 week period) were assessed based on COMP and on HAM-D, BDI and HADS-D scores alone. Compared to the control arm, a significant, positive effect in COMP was observed for MT1 at T2. Both MT1 and MT2 were associated with significant positive effects (HAM-D and HADS-D scores). MT2 resulted in positive effects on BDI scores. No significant change in any depression score was detected in the placebo arm. Treatment continuation was associated with an effect increase (mean HAM-D score reduction of 60%) after 10 to 15 weeks of treatment.
This paper reviews and presents data of practical impact for those administering electroconvulsive therapy (ECT). In the first section, physical and physiological aspects of the stimulus as well as methods of stimulation are discussed. The second section deals with indications for ECT, efficacy and treatment modalities such as seizure duration, treatment frequency and total number of ECT applications. The last section is devoted to side effects, risks, comedication and comorbidity.
Previous research revealed substantial relations between the experience of childhood adversities and the development of borderline personality disorders (BPD) in adulthood. However, research about antecedents of adolescent BPD is still in its beginnings. Moreover, there is an ongoing controversy regarding transgenerational effects of childhood adversities and potential mediators.
We aim to investigate transgenerational effects of parental childhood experiences on the development of adolescent BPD within the next generation. Hereby, we are focusing on the investigation of differential effects of maternal and paternal experiences of childhood adversities on adolescent BPD and on underlying mechanisms.
We consecutively recruited 91 female inpatients (Mage = 15.6 years) from the Department of Child and Adolescent Psychiatry, University Hospital Heidelberg, as well as 87 mothers and 59 fathers. Childhood adversities were assessed for parents and adolescents with the German Childhood Experiences of Care and Abuse Questionnaire, adolescent BPD by means of structured clinical interviews (SKID II).
Our results are in favor of a transgenerational effect of parental childhood adversities on the development of adolescent BPD. This effect turned out to be stronger for paternal than for maternal childhood adversities. Moreover, paternal childhood adversities revealed to be related to experiences of childhood adversities within the next generation.
Our results underline the importance of taking the family environment into consideration when developing prevention and treatment programs for adolescent BPD.
Our aim was to identify areas of improvement for current Opioid Maintenance Treatment (OMT) approaches, by analysing European Quality Audit of Opioid Treatment (EQUATOR) data from 8 European countries (Austria, Denmark, France, Germany, Norway, Portugal, Sweden, UK).
A standardised face-to-face survey was administered to OMT patients (OMT-P) and active opioid user (AOU). Reasons for entering and staying out of OMT, rules pertaining to OMT, and factors facilitating OMT retention were compared between countries, and between OMT-P and AOU groups. Both groups were divided into those who never had OMT before [un-experienced OMT-P (n=573) and AOU (n=360)] and those who had been maintained at least once [experienced OMT-P (n=746) and AOU (n=377)].
Motives for starting OMT vary distinctly between countries (p≤0.001). Transnationally, experienced AOU reported concerns about their ability to follow treatment rules and negative treatment experiences as decisive reasons for staying out of OMT. Greater flexibility, less pressure to reduce their treatment dose and greater treatment structure were ranked significantly higher by experienced compared to un-experienced OMT-P as factors that might facilitate treatment retention (p≤0.05).
The major strength of this investigation was the homogenous methodology applied in all countries, which enabled new insights in variations between treatment systems and their impact on patient outcome. Treatment systems need to aim an optimal balance between flexibility and structure. Standardised approaches that still permit tailoring treatment to individual patient needs are crucial to yield maximum benefit for patients, and reduce the considerable societal economic burden of addiction.
The study examined the developmental trajectories of deliberate self-harm behavior (e.g. of non-suicidal self-injury, suicidality and substance use) in a community sample of 514 adolescents from 14.5 to 16.5 years of age. Data were taken from the German sample of the Saving and Empowering Young Lives in Europe study (SEYLE; Wasserman et al., 2010) and its consecutive follow-up assessments. Using general growth mixture modeling, distinctive classes for each self-harm behavior were identified. The high risk non-suicidal self-injury class as well as the high risk suicidality class demonstrated high initial values with a gradual decrease over adolescence. The substance use high risk class had a low initial value and presented acceleration with time. The high overlap between the three high-risk classes supports the notion that certain personality traits such as affective dysregulation or impulsivity may underlie these three behaviors. Compared to the low or moderate risk classes, individuals belonging to high risk classes revealed significantly higher scores in the SCID-II questionnaire for DSM-IV borderline personality disorder.
Non-suicidal self-injury (NSSI) is an increasing phenomenon among adolescents. So far, comparable data on prevalence and psychosocial correlates are still rare due to different definitions, study samples, and measures.
To investigate the prevalence and associated psychosocial factors of occasional and repetitive non-suicidal self-injury (NSSI) and its relationship to suicide attempts in a representative adolescent samples from eleven European countries.
Cross sectional assessment of adolescents was performed within the European Union funded project, Saving and Empowering Young Lives in Europe (SEYLE), which was conducted in eleven European countries. The representative sample comprised 12,068 adolescents (F/M: 6,717/5,351; mean age: 14.9±0.89) recruited from randomly selected schools. Frequency of NSSI was assessed by a modified version of the Deliberate Self-Harm Inventory (DSHI) and the Paykel Suicide Scale. Additionally, a broad range of demographic, social and psychological factors was assessed.
Overall lifetime prevalence of NSSI was 27.6%; 19.7% reported occasional NSSI and 7.8% repetitive NSSI. Lifetime prevalence ranged from 17.1% to 38.6% across countries. Suicidality, anxiety and depression had the highest odds ratios for both occasional and repetitive NSSI.
Results suggest high lifetime prevalence of NSSI in European adolescents, with significant country differences. A strong association of NSSI with both psychopathology and risk-behaviours, including family-related neglect and peer-related rejection/victimization could be found. These results, combined with the observed gender and country differences, support the need for a multidimensional approach to better understand the development of NSSI and facilitate culturally adapted prevention/intervention.