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This chapter addresses a special category of cases in which an asserted patent is, or has been declared to be, essential to the implementation of a collaboratively developed voluntary consensus standard, and the holder of that patent has agreed to license it to implementers of the standard on terms that are fair, reasonable, and nondiscriminatory (FRAND).This chapter explores how the existence of such a FRAND commitment may affect a patent holder’s entitlement to monetary damages and injunctive relief. In addition to issues of patent law, remedies law, and contracts law, we consider the effect of competition law on this issue.
As depression has a recurrent course, relapse and recurrence prevention is essential.
In our randomised controlled trial (registered with the Nederlands trial register, identifier: NTR1907), we found that adding preventive cognitive therapy (PCT) to maintenance antidepressants (PCT+AD) yielded substantial protective effects versus antidepressants only in individuals with recurrent depression. Antidepressants were not superior to PCT while tapering antidepressants (PCT/−AD). To inform decision-makers on treatment allocation, we present the corresponding cost-effectiveness, cost-utility and budget impact.
Data were analysed (n = 289) using a societal perspective with 24-months of follow-up, with depression-free days and quality-adjusted life years (QALYs) as health outcomes. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were derived to provide information about cost-effectiveness. The budget impact was examined with a health economic simulation model.
Mean total costs over 24 months were €6814, €10 264 and €13 282 for AD+PCT, antidepressants only and PCT/−AD, respectively. Compared with antidepressants only, PCT+AD resulted in significant improvements in depression-free days but not QALYs. Health gains did not significantly favour antidepressants only versus PCT/−AD. High probabilities were found that PCT+AD versus antidepressants only and antidepressants only versus PCT/−AD were dominant with low willingness-to-pay thresholds. The budget impact analysis showed decreased societal costs for PCT+AD versus antidepressants only and for antidepressants only versus PCT/−AD.
Adding PCT to antidepressants is cost-effective over 24 months and PCT with guided tapering of antidepressants in long-term users might result in extra costs. Future studies examining costs and effects of antidepressants versus psychological interventions over a longer period may identify a break-even point where PCT/−AD will become cost-effective.
Declaration of interest
C.L.H.B. is co-editor of PLOS One and receives no honorarium for this role. She is also co-developer of the Dutch multidisciplinary clinical guideline for anxiety and depression, for which she receives no remuneration. She is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. C.L.H.B. has presented keynote addresses at conferences, such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some including a fee. She receives royalties from her books and co-edited books and she developed preventive cognitive therapy on the basis of the cognitive model of A. T. Beck. W.A.N. has received grants from the Netherlands Organisation for Health Research and Development and the European Union and honoraria and speakers' fees from Lundbeck and Aristo Pharma, and has served as a consultant for Daleco Pharma.
For the past quarter of a century, Frank et al.’s (1991) consensus-based definitions of major depressive disorder (MDD) episode, remission, recovery, relapse and recurrence have been the paramount driving forces for consistency in MDD research as well as in clinical practice. This study aims to review the evidence for the empirical validation of Frank et al.’s proposed concept definitions and to discuss evidence-based modifications.
A literature search of Web of Science and PubMed from 1/1/1991 to 08/30/2017 identified all publications which referenced Frank et al.’s request for definition validation. Publications with data relevant for validation were included and checked for referencing other studies providing such data.
A total of 56 studies involving 39 315 subjects were included, mainly presenting data to validate the severity and duration thresholds for defining remission and recovery. Most studies indicated that the severity threshold for defining remission should decrease. Additionally, specific duration thresholds to separate remission from recovery did not add any predictive value to the notion that increased remission duration alleviates the risk of reoccurrence of depressive symptoms. Only limited data were available to validate the severity and duration criteria for defining a depressive episode.
Remission can best be defined as a less symptomatic state than previously assumed (Hamilton Rating Scale for Depression, 17-item version (HAMD-17) ⩽4 instead of ⩽7), without applying a duration criterion. Duration thresholds to separate remission from recovery are not meaningful. The minimal duration of depressive symptoms to define a depressive episode should be longer than 2 weeks, although further studies are required to recommend an exact duration threshold. These results are relevant for researchers and clinicians aiming to use evidence-based depression outcomes.
The vulnerability hypothesis suggests that impairments after remission of depressive episodes reflect a pre-existing vulnerability, while the scar hypothesis proposes that depression leaves residual impairments that confer risk of subsequent episodes. We prospectively examined vulnerability and scar effects in mental and physical functioning in a representative Dutch population sample.
Three waves were used from the Netherlands Mental Health Survey and Incidence Study-2, a population-based study with a 6-years follow-up. Mental and physical functioning were assessed with the Medical Outcomes Study Short Form (SF-36). Major depressive disorder (MDD) was assessed with the Composite International Diagnostic Interview 3.0. Vulnerability effects were examined by comparing healthy controls (n = 2826) with individuals who developed a first-onset depressive episode during first follow-up but did not have a lifetime diagnosis of MDD at baseline (n = 181). Scarring effects were examined by comparing pre- and post-morbid functioning in individuals who developed a depressive episode after baseline that was remitted at the third wave (n = 108).
Both mental (B = −5.4, s.e. = 0.9, p < 0.001) and physical functioning (B = −8.2, s.e. = 1.1, p < 0.001) at baseline were lower in individuals who developed a first depressive episode after baseline compared with healthy controls. This effect was most pronounced in people who developed a severe episode. No firm evidence of scarring in mental or physical functioning was found. In unadjusted analyses, physical functioning was still lowered post-morbidly (B = −5.1, s.e. = 2.1, p = 0.014), but this effect disappeared in adjusted analyses.
Functional impairments after remission of depression seem to reflect a pre-existing vulnerability rather than a scar.
A substantial proportion of persons with mental disorders seek treatment from complementary and alternative medicine (CAM) professionals. However, data on how CAM contacts vary across countries, mental disorders and their severity, and health care settings is largely lacking. The aim was therefore to investigate the prevalence of contacts with CAM providers in a large cross-national sample of persons with 12-month mental disorders.
In the World Mental Health Surveys, the Composite International Diagnostic Interview was administered to determine the presence of past 12 month mental disorders in 138 801 participants aged 18–100 derived from representative general population samples. Participants were recruited between 2001 and 2012. Rates of self-reported CAM contacts for each of the 28 surveys across 25 countries and 12 mental disorder groups were calculated for all persons with past 12-month mental disorders. Mental disorders were grouped into mood disorders, anxiety disorders or behavioural disorders, and further divided by severity levels. Satisfaction with conventional care was also compared with CAM contact satisfaction.
An estimated 3.6% (standard error 0.2%) of persons with a past 12-month mental disorder reported a CAM contact, which was two times higher in high-income countries (4.6%; standard error 0.3%) than in low- and middle-income countries (2.3%; standard error 0.2%). CAM contacts were largely comparable for different disorder types, but particularly high in persons receiving conventional care (8.6–17.8%). CAM contacts increased with increasing mental disorder severity. Among persons receiving specialist mental health care, CAM contacts were reported by 14.0% for severe mood disorders, 16.2% for severe anxiety disorders and 22.5% for severe behavioural disorders. Satisfaction with care was comparable with respect to CAM contacts (78.3%) and conventional care (75.6%) in persons that received both.
CAM contacts are common in persons with severe mental disorders, in high-income countries, and in persons receiving conventional care. Our findings support the notion of CAM as largely complementary but are in contrast to suggestions that this concerns person with only mild, transient complaints. There was no indication that persons were less satisfied by CAM visits than by receiving conventional care. We encourage health care professionals in conventional settings to openly discuss the care patients are receiving, whether conventional or not, and their reasons for doing so.
Literature has shown that obesity, metabolic syndrome and inflammation are associated with depression, however, evidence suggests that these associations are specific to atypical depression. Which of the atypical symptoms are driving associations with obesity-related outcomes and inflammation is unknown. We evaluated associations between individual symptoms of depression (both atypical and non-atypical) and body mass index (BMI), metabolic syndrome components and inflammatory markers.
We included 808 persons with a current diagnosis of depression participating in the Netherlands Study of Depression and Anxiety (67% female, mean age 41.6 years). Depressive symptoms were derived from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Univariable and multivariable regression analyses adjusting for sex, age, educational level, depression severity, current smoking, physical activity, anti-inflammatory medication use, and statin use were performed.
Increased appetite was positively associated with BMI, number of metabolic syndrome components, waist circumference, C-reactive protein and tumor necrosis factor-α. Decreased appetite was negatively associated with BMI and waist circumference. Psychomotor retardation was positively associated with BMI, high-density lipoprotein cholesterol and triglycerides, and insomnia with number of metabolic syndrome components.
Increased appetite – in the context of a depressive episode – was the only symptom that was associated with both metabolic as well as inflammatory markers, and could be a key feature of an immuno-metabolic form of depression. This immuno-metabolic depression should be considered in clinical trials evaluating effectiveness of compounds targeting metabolic and inflammatory pathways or lifestyle interventions.
Research on post-traumatic stress disorder (PTSD) course finds a substantial proportion of cases remit within 6 months, a majority within 2 years, and a substantial minority persists for many years. Results are inconsistent about pre-trauma predictors.
The WHO World Mental Health surveys assessed lifetime DSM-IV PTSD presence-course after one randomly-selected trauma, allowing retrospective estimates of PTSD duration. Prior traumas, childhood adversities (CAs), and other lifetime DSM-IV mental disorders were examined as predictors using discrete-time person-month survival analysis among the 1575 respondents with lifetime PTSD.
20%, 27%, and 50% of cases recovered within 3, 6, and 24 months and 77% within 10 years (the longest duration allowing stable estimates). Time-related recall bias was found largely for recoveries after 24 months. Recovery was weakly related to most trauma types other than very low [odds-ratio (OR) 0.2–0.3] early-recovery (within 24 months) associated with purposefully injuring/torturing/killing and witnessing atrocities and very low later-recovery (25+ months) associated with being kidnapped. The significant ORs for prior traumas, CAs, and mental disorders were generally inconsistent between early- and later-recovery models. Cross-validated versions of final models nonetheless discriminated significantly between the 50% of respondents with highest and lowest predicted probabilities of both early-recovery (66–55% v. 43%) and later-recovery (75–68% v. 39%).
We found PTSD recovery trajectories similar to those in previous studies. The weak associations of pre-trauma factors with recovery, also consistent with previous studies, presumably are due to stronger influences of post-trauma factors.
Sexual assault is a global concern with post-traumatic stress disorder (PTSD), one of the common sequelae. Early intervention can help prevent PTSD, making identification of those at high risk for the disorder a priority. Lack of representative sampling of both sexual assault survivors and sexual assaults in prior studies might have reduced the ability to develop accurate prediction models for early identification of high-risk sexual assault survivors.
Data come from 12 face-to-face, cross-sectional surveys of community-dwelling adults conducted in 11 countries. Analysis was based on the data from the 411 women from these surveys for whom sexual assault was the randomly selected lifetime traumatic event (TE). Seven classes of predictors were assessed: socio-demographics, characteristics of the assault, the respondent's retrospective perception that she could have prevented the assault, other prior lifetime TEs, exposure to childhood family adversities and prior mental disorders.
Prevalence of Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) PTSD associated with randomly selected sexual assaults was 20.2%. PTSD was more common for repeated than single-occurrence victimization and positively associated with prior TEs and childhood adversities. Respondent's perception that she could have prevented the assault interacted with history of mental disorder such that it reduced odds of PTSD, but only among women without prior disorders (odds ratio 0.2, 95% confidence interval 0.1–0.9). The final model estimated that 40.3% of women with PTSD would be found among the 10% with the highest predicted risk.
Whether counterfactual preventability cognitions are adaptive may depend on mental health history. Predictive modelling may be useful in targeting high-risk women for preventive interventions.
Although specific phobia is highly prevalent, associated with impairment, and an important risk factor for the development of other mental disorders, cross-national epidemiological data are scarce, especially from low- and middle-income countries. This paper presents epidemiological data from 22 low-, lower-middle-, upper-middle- and high-income countries.
Data came from 25 representative population-based surveys conducted in 22 countries (2001–2011) as part of the World Health Organization World Mental Health Surveys initiative (n = 124 902). The presence of specific phobia as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition was evaluated using the World Health Organization Composite International Diagnostic Interview.
The cross-national lifetime and 12-month prevalence rates of specific phobia were, respectively, 7.4% and 5.5%, being higher in females (9.8 and 7.7%) than in males (4.9% and 3.3%) and higher in high- and higher-middle-income countries than in low-/lower-middle-income countries. The median age of onset was young (8 years). Of the 12-month patients, 18.7% reported severe role impairment (13.3–21.9% across income groups) and 23.1% reported any treatment (9.6–30.1% across income groups). Lifetime co-morbidity was observed in 60.5% of those with lifetime specific phobia, with the onset of specific phobia preceding the other disorder in most cases (72.6%). Interestingly, rates of impairment, treatment use and co-morbidity increased with the number of fear subtypes.
Specific phobia is common and associated with impairment in a considerable percentage of cases. Importantly, specific phobia often precedes the onset of other mental disorders, making it a possible early-life indicator of psychopathology vulnerability.
A small ice-dammed lake near Søndre Strømfjord, West Greenland, drained suddenly during the night of 15–16 July 1988. This drainage was observed from within the lake basin near the tunnel mouth. The drainage had four main effects: the collapse of adjacent moraine ridges; the shearing of ice around the tunnel mouth; rapid incision of the lake bed; and the transport of sediment from the lake basin into the glacier. All of the above were confined to a period of 15–30 min following the exposure of a circular tunnel c. 6 m in diameter.
It is a commonplace to link Homer with tragedy. Plato calls Homer the first tragedian, Aristotle praises the dramatic concentration of his plots, and pseudo-Plutarch claims that in Homer we find ‘all elements of tragedy: great and unexpected deeds, epiphanies of gods, and speeches full of thought and representing all kind of characters’. Likewise, modern critics write studies on Nature and Culture in the Iliad. The Tragedy of Hector, ‘Tragic Form and Feeling in the Iliad’, ‘Homeric Epic and the Tragic Moment’, and Homer and the Dual Mode of the Tragic.
Research on post-traumatic stress disorder (PTSD) following natural and human-made disasters has been undertaken for more than three decades. Although PTSD prevalence estimates vary widely, most are in the 20–40% range in disaster-focused studies but considerably lower (3–5%) in the few general population epidemiological surveys that evaluated disaster-related PTSD as part of a broader clinical assessment. The World Mental Health (WMH) Surveys provide an opportunity to examine disaster-related PTSD in representative general population surveys across a much wider range of sites than in previous studies.
Although disaster-related PTSD was evaluated in 18 WMH surveys, only six in high-income countries had enough respondents for a risk factor analysis. Predictors considered were socio-demographics, disaster characteristics, and pre-disaster vulnerability factors (childhood family adversities, prior traumatic experiences, and prior mental disorders).
Disaster-related PTSD prevalence was 0.0–3.8% among adult (ages 18+) WMH respondents and was significantly related to high education, serious injury or death of someone close, forced displacement from home, and pre-existing vulnerabilities (prior childhood family adversities, other traumas, and mental disorders). Of PTSD cases 44.5% were among the 5% of respondents classified by the model as having highest PTSD risk.
Disaster-related PTSD is uncommon in high-income WMH countries. Risk factors are consistent with prior research: severity of exposure, history of prior stress exposure, and pre-existing mental disorders. The high concentration of PTSD among respondents with high predicted risk in our model supports the focus of screening assessments that identify disaster survivors most in need of preventive interventions.
This paper reports the first chronological assessment of the Christian catacombs of Rome by radiocarbon dating. The organic materials dated were found in a set of burial rooms in the so-called Liberian region of the catacombs of St. Callixtus on the Appian Way. 14C dating of small samples by accelerator mass spectrometry (AMS) represents a major advance over traditional archaeological dating methods used in catacomb archaeology; however, AMS 14C dating raises questions about sample reliability and chronological evaluation. We briefly explore these questions.
A high-resolution atmospheric radiocarbon record has been obtained for the interval of 17–36 kyr from U/Th-dated aragonite sediment of Lake Lisan. Reservoir age corrections were applied with reservoir ages of 200, 1250, and 2000 yr, which correlate with the different water levels of the lake. The present 14C record for Lake Lisan shows near resemblance with that of Lake Suigetsu: both converge to the value of Δ14C ∼0‰ at 32 kyr cal BP. Both also show significant differences compared to other reported high-resolution 14C records (e.g. Iceland Sea, Cariaco basin, and Bahamas speleothem). This inconsistency should be addressed by re-assessment of the basic assumptions behind the determination of calendar ages of the various records.
In the radiocarbon accelerator mass spectrometry (14C AMS) analysis of gases obtained in a dry extraction from a 52–m Antarctic ice core, we observed 14CO2 and 14CO concentrations decreasing with depth. The concentrations are explained in terms of in-situ production by neutrons and captured muons in ablating ice. The ratio of the 14CO2 concentration to that of 14CO has been found to be constant at 1.9 ± 0.3. The ablation rates obtained of 42 ± 18 cm.yr−1 and 40 ± 13 cm.yr−1 for the neutron and muon components, respectively, are about three times higher than observed from stake readings. The discrepancy may point to an incomplete extraction of the dry extraction method. Using the constant ratio in 14CO2 and 14CO concentrations we correct for the in-situ component in the trapped 14CO2 and deduce an age of 10,300 ± 900 BP for the ice core.
We made a comparative study of AMS 14C ages of organic deposits (minerotrophic peats and gyttjas) and macrofossils in order to evaluate the magnitude of a number of sources of error that may be present in bulk sediment samples. The consistency of 14C ages found for coexisting macrofossils suggests that they are unlikely to record disturbances. Some of our gyttja samples yielded an age 0.2–0.6 ka 14C years too old due to hardwater effect. We also found an aging effect in several bulk samples with a high admixture of siliciclastic material; this is attributed to fluvial input of reworked, older organic debris. Rejuvenation of bulk material as a result of root contamination occurs mainly in samples overlain by slowly accumulated deposits, and particularly in samples affected by (sub)recent roots.
In AMS measurements on small (m 400 μg) carbon samples, an m-dependence has been noted for the 14C/12C and 13C/12C ratios that is due to the combined effect of contamination and fractionation. A simple formalism is presented to describe the phenomena and to correct measurements on unknowns for their effect.
Maps of accumulation rates of freshwater diatoms and opal phytoliths in the surface sediments of the Zaire fan show that both types of microfossils were supplied to the ocean floor by the Zaire River, and that opal phytoliths also have a southern source, probably the region of the Namibian desert. The PhFD ratio, of opal phytoliths to freshwater diatoms, can be regarded as an aridity index for equatorial Africa, and probably for large parts of the central and southern Atlantic. In two cores, the record of the PhFD ratio indicates humidity ca 225–190 ka BP, aridity 190–135 ka BP with maxima ca 170 and 140 ka BP and a humid excursion 150 ka BP, an increase in humidity 115 ka BP, a less humid period 90–30 ka BP, more humidity ca 30–17 ka BP with possibly more arid intervals ca 22.5 and 20 ka bp. In general, glacial (sub) stages were more arid and interglacial (sub) stages more humid. For the last 20 ka, the PhFD ratio corresponds closely with the known climatic events in tropical Africa.