We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save 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 saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
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 saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved 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.
Current ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties.
Objectives
To investigate efficacy, safety, and pharmacokinetics of KET01 in TRD.
Methods
KET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline.
Results
KET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p<0.00000000001). KET01-02 trial; no differences in CADSS score (range: 0.2 to 1.3), and heart rate and blood pressure were observed between the groups on Day 1 and beyond. 10%, 12%, and 15% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 groups, respectively had CADSS score >4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively.
Conclusions
Oral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD.
Disclosure of Interest
C. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health
It is not sufficient to merely publish regulations and strictly control them to improve the living conditions of farm animals. The farmer must receive precise information, understand the individual measures and be able to act with personal responsibility. A new animal welfare law has been in force in Austria since the 1st of January 2005. A system of self-evaluation is being developed for putting these new legal requirements into practice. The aim of this self-evaluation system is to enable every farmer to personally check his animal housing system against the given standards. This independent work motivates the farmer and makes him aware of animal welfare issues. This new strategy for the implementation of animal welfare law was originally developed, tested and found to be successful by the Federal Administration of the Austrian Province of Vorarlberg. Self-evaluation is to be carried out by means of specific checklists and manuals. Checklists and manuals are currently being drawn up for cattle, pigs, poultry, sheep and goats. The checklists and manuals will include all of the requirements of Austrian animal welfare legislation and will be formulated in easily understandable questions with ‘yes’ or ‘no’ answers. The manuals will describe the methods for assessing legal requirements on the farm as well as the conditions for compliance with legislation, and give advice on how to improve the state of animal welfare on the farm. This paper gives an example of the self-evaluation system for cattle farming.
Research on assistive home technology (AT) aims to reduce care costs and increase quality of life of people with dementia. Currently it is unclear what the needs of people with dementia are and what kind of support they desire. The reported survey aims to identify personal attitudes towards AT in daily living: As how disturbing is the loss of competence in activities of daily living (ADL) experienced? For which ADLs would AT be accepted? Which kind of sensor technology and interaction devices would be tolerated at home? Interviews with open questions and rating scales were conducted with 53 persons (m = 14, f = 39; aged 19–59). Subjects were professional care givers (n = 23), relatives of people with dementia (n = 15), and persons without dementia background (n = 15). The answers were evaluated statistically. Loosing the ability to take care of own body hygiene was judged as most disturbing. Washing clothes was judged as least disturbing. In general people preferred being helped by family members. However, AT was mostly preferred over professional care. People can best imagine AT help for using the telephone and managing medicine taking. Help by AT is nearly excluded for social relationships and finances. Transponders on objects are accepted best, closely followed by motion sensors. Video sensors are approved least. The PDA is the most accepted shape of AT. When developing AT, it is worthwhile to include potential user groups in decisions about areas of support as well as technical design to increase acceptance.
Accurately dating when people first colonized new areas is vital for understanding the pace of past cultural and environmental changes, including questions of mobility, human impacts and human responses to climate change. Establishing effective chronologies of these events requires the synthesis of multiple radiocarbon (14C) dates. Various “chronometric hygiene” protocols have been used to refine 14C dating of island colonization, but they can discard up to 95% of available 14C dates leaving very small datasets for further analysis. Despite their foundation in sound theory, without independent tests we cannot know if these protocols are apt, too strict or too lax. In Iceland, an ice core-dated tephrochronology of the archaeology of first settlement enables us to evaluate the accuracy of 14C chronologies. This approach demonstrated that the inclusion of a wider range of 14C samples in Bayesian models improves the precision, but does not affect the model outcome. Therefore, based on our assessments, we advocate a new protocol that works with a much wider range of samples and where outlying 14C dates are systematically disqualified using Bayesian Outlier Models. We show that this approach can produce robust termini ante quos for colonization events and may be usefully applied elsewhere.
A number of publications have discussed approaches to training the scientific workforce in comparative effectiveness research (CER) and patient-centered outcomes research (PCOR). To meet this need, funders have offered resources for developing educational materials and establishing training programs. To extend these efforts into specific researcher communities, the Agency for Healthcare Research and Quality developed an R25 Funding Opportunity Announcement that called for basic, advanced, and experiential training for a specific researcher community in collaboration with associated program partners. This paper describes the strategies developed by the 5 subsequently funded programs, their specific researcher communities and program partners, and the challenges associated with developing in-person and online programs. We focus on lessons learned that can be translated into developing training programs nationwide and on training for the special populations of interest. We also discuss the creation of a sustainable network for training and the conduct of comparative effectiveness research/patient-centered outcomes research in targeted communities.
Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.
Methods
In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.
Results
Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.
Conclusion
Our findings show that 5-HT2AR activation by LSD leads to a hippocampal–prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.
A series of phase transformations of a novel fluoroaluminosilicate glass forming a range of fluorapatite glass-ceramics on sintering are reported. The sintering process induces formation of fluorapatite, mullite, and anorthite phases within the amorphous silicate matrices of the glass-ceramics. The fluoroaluminosilicate glass, SiO2–Al2O3–P2O5–CaO–CaF2, is prepared from waste materials, such as rice husk ash, pacific oyster shells, and disposable aluminium cans. The thermally induced crystallographic and microstructure evolution of the fluoroaluminosilicate glass towards the fluorapatite glass-ceramics, with applications in dental and bone restoration, are investigated by powder X-ray diffraction and small-angle neutron-scattering techniques.
Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results.
Methods:
A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature.
Results:
Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted.
Conclusion:
Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.
This study aimed to link expression patterns of AQP1, AQP5, Bcl-2 and p16 to clinicopathological characteristics of oro-hypopharyngeal squamous cell carcinomas.
Methods:
Immunohistochemical expression of AQP1, AQP5, Bcl-2 and p16 was investigated in 107 consecutive oro-hypopharyngeal squamous cell carcinoma cases. Molecular interrelationship and correlations with clinicopathological parameters and survival were computed.
Results:
AQP1 was expressed exclusively by a subgroup of basaloid-like squamous cell carcinomas. AQP5 was detected in 25.2 per cent of the samples, showing significant association with the absence of p16 and Bcl-2 (p = 0.018; p = 0.010). In multivariate analysis, overexpression of p16 was significantly correlated with favourable overall survival (p = 0.014).
Conclusion:
AQP5 defined a subset of patients with Bcl-2-negative and p16-negative tumours with a poor clinical outcome. AQP1 was found to be a marker of a subgroup of aggressive basaloid-like squamous cell carcinomas. These findings suggest that AQP1 and AQP5 are interesting candidates for further studies on risk group classification and personalised treatment of oro-hypopharyngeal squamous cell carcinomas.
The epidemiology of varicella is believed to differ between temperate and tropical countries. We conducted a varicella seroprevalence study in elementary and college students in the US territory of American Samoa before introduction of a routine varicella vaccination programme. Sera from 515 elementary and 208 college students were tested for the presence of varicella-zoster virus (VZV) IgG antibodies. VZV seroprevalence increased with age from 76·0% in the 4–6 years group to 97·7% in those aged ⩾23 years. Reported history of varicella disease for elementary students was significantly associated with VZV seropositivity. The positive and negative predictive values of varicella disease history were 93·4% and 36·4%, respectively, in elementary students and 97·6% and 3·0%, respectively, in college students. VZV seroprevalence in this Pacific island appears to be similar to that in temperate countries and suggests endemic VZV circulation.
LOFT (Large Observatory For X-ray Timing) is one of the four candidate missions currentlyunder assessment study for the M3 mission in ESAs Cosmic Vision program to be launched in2024. LOFT will carry two instruments with prime sensitivity in the 2–30 keV range: a 10m2 class large area detector (LAD) with a <1° collimated field of viewand a wide field monitor (WFM) instrument. The WFM is based on the coded mask principle,and 5 camera units will provide coverage of more than 1/3 of the sky. The prime goal ofthe WFM is to detect transient sources to be observed by the LAD. With its wide field ofview and good energy resolution of <500 eV, the WFM will be an excellent instrumentfor detecting and studying GRBs and X-ray flashes. The WFM will be able to detect~150 gamma ray bursts per year, and a burst alert system will enable thedistribution of ~100 GRB positions per year with a ~1 arcmin locationaccuracy within 30 s of the burst.
The objective of the present study was to compare the performance of seven different, widely applied crop models in predicting heat and drought stress effects. The study was part of a recent suite of model inter-comparisons initiated at European level and constitutes a component that has been lacking in the analysis of sources of uncertainties in crop models used to study the impacts of climate change. There was a specific focus on the sensitivity of models for winter wheat and maize to extreme weather conditions (heat and drought) during the short but critical period of 2 weeks after the start of flowering. Two locations in Austria, representing different agro-climatic zones and soil conditions, were included in the simulations over 2 years, 2003 and 2004, exhibiting contrasting weather conditions. In addition, soil management was modified at both sites by following either ploughing or minimum tillage. Since no comprehensive field experimental data sets were available, a relative comparison of simulated grain yields and soil moisture contents under defined weather scenarios with modified temperatures and precipitation was performed for a 2-week period after flowering. The results may help to reduce the uncertainty of simulated crop yields to extreme weather conditions through better understanding of the models’ behaviour. Although the crop models considered (DSSAT, EPIC, WOFOST, AQUACROP, FASSET, HERMES and CROPSYST) mostly showed similar trends in simulated grain yields for the different weather scenarios, it was obvious that heat and drought stress caused by changes in temperature and/or precipitation for a short period of 2 weeks resulted in different grain yields simulated by different models. The present study also revealed that the models responded differently to changes in soil tillage practices, which affected soil water storage capacity.
A new subspecies of Ornithoptera croesus Wallace, O. c. toeantei, is described from Morotai Island, Indonesia; an annotated illustration of a gynandromorph of O. croesus lydius Felder from Halmaheira Island is presented.
Post-attack injections of full- and half-strength Silvisar 510 (cacodylic acid) appear to inhibit populations of Dendroctonus rufipennis (Kirby) more effectively than quarter- and tenth-strength dilutions. Arsenic concentrations in the phloem were highest in the full-strength treatments and progressively decreased in the lesser strength treatments. Arsenic concentrations in the phloem were generally highest just above the frill while concentrations at 20 ft and higher above the frill were significantly lower than those just above the frill. Arsenic concentrations in the needles were highest in the full- and half-strength treatments and decreased progressively in the lesser strength treatments. Concentrations in the needles were essentially equal in the upper and lower portions of the crown. Arsenic concentrations in the soil were not affected by the treatments.
To examine the reliability and convergent validity of physical activity (PA) and inactivity estimates obtained with the past-week Modifiable Activity Questionnaire (PWMAQ).
Design
The PWMAQ, an interviewer-administered questionnaire, was administered twice, one week apart, during visits 3 and 4 of six total visits. Intra-class correlation coefficients (ICC) between administrations of the PWMAQ were used to assess the reliability of summary estimates. Spearman rank-order correlation coefficients (ρ) were used to examine the associations of PWMAQ summary estimates with temporally matched and averaged accelerometer data in all participants and then stratified by whether the data were reflective of usual PA.
Setting
Data were obtained from the Evaluation of Physical Activity Measures in Middle-Aged Women (PAW) study.
Subjects
Sixty-six women, mean age 52·6 (sd 5·4) years.
Results
The reliability of the PWMAQ physical inactivity estimate suggested substantial agreement over one week (ICC = 0·77, 95 % CI 0·57, 0·82; P < 0·0001). With the exception of light-intensity PA, the PWMAQ leisure PA estimate was significantly associated with averaged accelerometer data (ρ = 0·33–0·76; P < 0·05). For both temporally matched and averaged accelerometer data, correlation coefficients were higher between the PWMAQ estimate and moderate-walk- to vigorous-intensity PA in those who indicated that reported activity was reflective of usual PA; however, the association with moderate-lifestyle-intensity PA was higher in those reporting that data were not reflective.
Conclusions
The PWMAQ is a reliable and valid measure of leisure PA levels in middle-aged women and supports subsequent studies evaluating this questionnaire in other population subgroups.
We report on a measles outbreak originating in an anthroposophic community in Austria, 2008. A total of 394 (94·9%) cases fulfilled the outbreak case definition including 168 cases affiliated to the anthroposophic community. The source case was a school pupil from Switzerland. The Austrian outbreak strain was genotype D5, indistinguishable from the Swiss outbreak strain. A school-based retrospective cohort study in the anthroposophic school demonstrated a vaccine effectiveness of 97·3% in pupils who had received a single dose of measles-containing vaccine and 100% in those who had received two doses. The vaccination coverage of the cases in the anthroposophic community was 0·6%. Of the 226 outbreak cases not belonging to the anthroposophic community, the 10–24 years age group was the most affected. Our findings underline the epidemiological significance of suboptimal vaccination coverage in anthroposophic communities and in older age groups of the general population in facilitating measles virus circulation. The findings of this outbreak investigation suggest that the WHO European Region is unlikely to achieve its 2010 target for measles and rubella elimination.