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Objective Existential isolation refers to an individual’s awareness of the unbridgeable gulf between oneself, other people, and the world. This kind of isolation has been found to be higher in individuals with nonnormative experiences, such as racial or sexual minorities. Bereaved individuals may experience a stronger sense of existential isolation and feel that no one shares their feelings or perceptions. However, research on bereaved people’s experiences of existential isolation and its effects on post-loss adaptation is scarce. This study aims to validate the German and Chinese versions of the Existential Isolation Scale, investigate cultural and gender differences in existential isolation, and explore the associations between existential isolation and prolonged grief symptoms in German-speaking and Chinese bereaved individuals. Methods A cross-sectional study with 267 Chinese and 158 German-speaking bereaved participants was conducted. The participants completed self-report questionnaires assessing existential isolation, prolonged grief symptoms, social networks, loneliness, and social acknowledgment. Results The results indicated that the German and Chinese versions of the Existential Isolation Scale demonstrated adequate validity and reliability. No cultural or gender differences (or their interaction) were found for existential isolation. Higher existential isolation was associated with elevated prolonged grief symptoms, which was further moderated by the cultural group. The relationship between existential isolation and prolonged grief symptoms was significant for the German-speaking bereaved people but not significant for those from China. Conclusion The findings highlight the role of existential isolation in the adaptation to bereavement and how different cultural backgrounds moderate the effect of existential isolation on post-loss reactions. Theoretical and practical implications are discussed.

Background: Bereavement can be considered a potentially traumatic experience, and concerns have been raised about conducting grief research responsibly online. Objective: Given that online research introduces new methodological opportunities and challenges, we aimed to develop a greater understanding of how bereaved individuals experience participation in online research. Method: One day after participation in an online grief study, 876 participants, bereaved on average for 40 months, received a ‘check-in’ email to support well-being and offer further contact if needed. Although not explicitly asked to respond if no help was needed, 300 participants sent email replies, with only six requesting support. These responses were analysed qualitatively using content analysis. Results: Results suggested that participants found it acceptable to be asked about their grief and while difficult emotions were frequently described in response to the questionnaires, these reactions were temporary. A range of positive reactions was also reported, including new realizations arising from completing the research and changes in thinking related to grief. Participants also wrote about their appreciation for the study and how it was carried out, as well as a desire to contribute more to the study and to help others in a similar position. Conclusions: We suggest that the use of the check-in email to support well-being following study completion, along with advice on preparing to take part, contributed to positive experiences of participation and we recommend these strategies for future studies. These findings could allay clinical concerns about conducting online research with vulnerable populations, as well as raising questions about the possible therapeutic impact of measurement.

Social support has been shown to facilitate adaptation after bereavement in some studies but not others. A felt sense of social disconnection may act as a barrier to the utilization of social support, perhaps explaining these discrepancies. Factorial and psychometric validity of the Oxford Grief-Social Disconnection Scale (OG-SD) was tested in a bereaved sample ( N = 676). A three-factor solution (negative interpretation of others’ reactions to grief expression, altered social self, and safety in solitude) fit the data best and demonstrated excellent psychometric validity. A second three-wave longitudinal sample ( N = 275) recruited 0 to 6 months following loss and followed up 6 and 12 months later completed measures of prolonged grief disorder, posttraumatic stress disorder, depression, and the OG-SD at each time point. High levels of baseline social disconnection were associated with concurrently high psychological distress. The extent to which social disconnection declined over time predicted resolution of psychological distress.

BackgroundThe COVID-19 pandemic is a mass bereavement event which has profoundly disrupted grief experiences. Understanding support needs and access to support among people bereaved at this time is crucial to ensuring appropriate bereavement support infrastructure.AimTo investigate grief experiences, support needs and use of formal and informal bereavement support among people bereaved during the pandemic.DesignBaseline results from a longitudinal survey. Support needs and experiences of accessing support are reported using descriptive statistics and thematic analysis of free-text data.Setting/Participants711 adults bereaved in the UK between March-December 2020, recruited via media, social media, national associations and community/charitable organisations.ResultsHigh-level needs for emotional support were identified. Most participants had not sought support from bereavement services (59%, n=422) or their GP (60%, n=428). Of participants who had sought such support, over half experienced difficulties accessing bereavement services (56%, n=149)/GP support (52%, n=135). 51% reported high/severe vulnerability in grief; among these, 74% were not accessing bereavement or mental-health services. Barriers included limited availability, lack of appropriate support, discomfort asking for help, and not knowing how to access services. 39% (n=279) experienced difficulties getting support from family/friends, including relational challenges, little face-to-face contact, and disrupted collective mourning. The perceived uniqueness of pandemic bereavement and wider societal strains exacerbated their isolation.ConclusionsPeople bereaved during the pandemic have high levels of support needs alongside difficulties accessing support. We recommend increased provision and tailoring of bereavement services, improved information on support options, and social/educational initiatives to bolster informal support and ameliorate isolation.Key statementsWhat is already known about the topic?– Features of pandemic bereavement, such as traumatic death experiences, exacerbate family distress and add to the complexity of grief.– In pre-pandemic times most people mainly relied on the informal support of friends and family to cope with their bereavement, but an estimated 40% required more formal therapeutic support from bereavement or mental health services.– Bereaved people experience difficulties getting the support that they need from bereavement services and their social networks.What this paper adds– Participants had high level needs for emotional support, especially dealing with/expressing feelings, with 51% experiencing high or severe vulnerability in grief; however, 74% of this group were not accessing formal bereavement service or mental health support.– Most participants had not tried to access bereavement services, for reasons such as lack of appropriate support, discomfort in asking for help and uncertainty of how to access services; of the 41% who tried, 56% experienced difficulties such as long waiting lists or ineligibility.– A substantial proportion of people (39%) reported difficulties accessing support from friends and family; reduced in-person contact affected the perceived quality of support and disrupted collective mourning practices, whilst the wider social difficulties of the pandemic compounded feelings of isolation.Implications for policy and practice– Further investment in the provision of tailored bereavement support is needed to meet the diverse needs and backgrounds of bereaved people, including support that is culturally and crisis/context competent, and group-based support for those with shared experiences and characteristics.– To raise awareness of support options, information on grief and bereavement services should be provided proactively following a death and made available in online and community settings, with GPs and other primary care providers better resourced to signpost to appropriate support.– Following compassionate communities approaches, expanded provision of informal community-based support and activities could help with isolation, whilst longer-term educational and societal initiatives are needed to bolster community support for people experiencing death, dying and bereavement.

Background COVID-19 represents a mass bereavement event, with 80,000+ excess UK deaths. The unprecedented clinical and social restrictions are potential risk factors for poor bereavement outcomes. This study investigates the bereavement experiences, support needs and support use of people bereaved during the pandemic.Methods Interim findings from the first round of a mixed methods longitudinal survey of people bereaved in the UK since 16March 2020. The survey was disseminated via media, social media, national associations and community/charitable organisations. Grief was assessed using the Adult Attitude to Grief Scale.Results 532 bereaved people participated (91% female). Place of death: hospital (55%), home (22%), care home (15%), hospice (5%); 46% of deaths were confirmed/suspected COVID-19. Experiences of end of life care varied: 23% were ‘never’ involved in decisions about their loved one’s care, 36% felt ‘not at all’ supported by healthcare professionals after the death, 51% were not provided with information about bereavement support. Respondents reported high levels of problems specific to the pandemic bereavement context (e.g. 56% unable to visit prior to death, 67% social isolation and loneliness). Over half of participants demonstrated ‘severe’ (28%) or ‘high’ (24%) levels of vulnerability in grief, and support needs were high/fairly high in six psycho-emotional domains (51% to 62%). COVID-19 deaths were associated with higher levels of bereavement problems (p

Objective: The study aimed to explore the content and features of loss-related memories in a sample of individuals bereaved by cancer with and without a probable diagnosis of prolonged grief disorder/persistent complex bereavement disorder (PGD/PCBD). Methods: Semi-structured interviews with 28 bereaved adults (PGD/PCBD = 12, NoPGD/PCBD = 16) were analysed using thematic analysis. Results: Three superordinate themes were identified: (1) intrusive imagery, (2) qualities of memory, and (3) triggers. Results showed that individuals suffering from probable PGD/PCBD reported a predominance of negative and upsetting memories, happy memories triggering pain and more negative intrusive imagery than those without PGD/PCBD. Conclusions: Bereavement by cancer can result in troubling intrusive memories that overshadow positive memories. Sufferers of PGD/PCBD are more likely to experience loss-related memories as negative and upsetting. Clinical approaches that utilise memory processing may be of particular relevance in this group.

Objective: The identification of modifiable cognitive antecedents of trajectories of grief is of clinical and theoretical interest. Method: The study gathered 3-wave data on 275 bereaved adults in the first 12–18 months postloss (T1 = 0–6 months, T2 = 6–12 months, T3 = 12–18 months). Participants completed measures of grief severity, cognitive factors (loss-related memory characteristics, negative appraisals, unhelpful coping strategies, and grief resilience), as well as measures of interpersonal individual differences (attachment and dependency). Latent growth mixture modeling was used to identify classes of grief trajectories. Predictors of class membership were identified using multinomial logistic regression and multigroup structural equation modeling. Results: Four latent classes were identified: 3 high grief classes (Stable, Low Adaptation, and High Adaptation) and a low grief class (Low Grief). When considered separately, variance in all four cognitive factors predicted membership of the high grief classes. When considered together, membership of the high grief classes was predicted by higher mean scores on memory characteristics. More negative appraisals predicted low or no adaptation from high grief severity. Losing a child also predicted membership to the stable class. Fast adaptation of high grief was predicted by a pattern of high memory characteristics but low engagement with unhelpful coping strategies. Conclusions: The findings have implications for clinical practice and point to early cognitive predictors of adaptation patterns in grief. Findings are consistent with cognitive models highlighting the importance of characteristics of memory, negative appraisals, and unhelpful coping strategies in the adaptation to highly negative life events., What is the public health significance of this article? The study identifies a number of modifiable cognitive predictors that are linked to grief severity and maintenance in the first months of loss. Targeting these cognitive predictors in the first 6 months of loss may prove helpful in facilitating grief adaptation.

This study examined the effectiveness of a novel cancer bereavement group. Twenty-seven participants attended a six-session cancer bereavement therapeutic group. Data were collected at baseline, intervention completion, and three-month follow-up. Grief intensity and symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety were reduced postintervention, and self-compassion increased. At follow-up, improvement remained for grief, PTSD, and depression. A small quasi-experimental waiting-list comparison group showed no change on any measure between baseline and waiting-list end. This study provides preliminary evidence that a brief therapeutic group is an effective intervention for cancer bereavement.

Background Cognitive behavioural correlates to bereavement-related mental health problems such a Prolonged Grief Disorder (PGD) and Posttraumatic Stress Disorder (PTSD) are of theoretical and clinical importance. Methods Individuals bereaved at least six months (N = 647) completed measures of loss-related cognitions and behaviours (i.e., loss-related memory characteristics, negative appraisals, coping strategies, grief resilience, and perceived social disconnection) and measures of PGD and PTSD symptoms. Individuals were assigned to one of four groups depending on probable clinical diagnoses (No-PGD/PTSD, PTSD, PGD, PGD+PTSD). Results Results indicated that higher loss-related memory characteristics and lower grief resilience increased the likelihood of a clinical problem. The PGD and PGD+PTSD groups reported significantly higher loss-related memory characteristics and appraisals compared to the PTSD group. Social disconnection increased the likelihood of comorbid PGD+PTSD in comparison to any other group. Conclusions Results indicate cognitive differences between loss-related cognitions, memory characteristics and coping strategies between PGD and PTSD, and points to distinct cognitive correlates to psychopathology following loss.

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

Evidence suggests that veterans with posttraumatic stress disorder (PTSD) have a poorer treatment response than nonveterans. In this study, we explored heterogeneity in treatment response for 960 veterans in the United Kingdom with PTSD who had been offered a residential intervention consisting of a mixture of group sessions and individual trauma-focused cognitive behavioral therapy (TF-CBT). The primary outcome was PTSD score on the Impact of Event Scale-Revised (IES-R). Covariates included depression, anxiety, anger, alcohol misuse, functional impairment, and sociodemographic characteristics. Follow-up occurred posttreatment at set time points for 12 months. We present predictors of PTSD severity at posttreatment and follow-up obtained using a latent class growth analysis to identify different treatment trajectories. Multinomial logistic regression models were used to identify covariates predicting class membership, and five classes were identified. Of participants, 71.3% belonged to three classes showing positive treatment responses, and 1.2% showed initial improvement but later relapsed. Additionally, 27.5% of participants were identified within a treatment-resistant class that showed little change in severity of presentation. Depression, anxiety, and having had a combat role during military service increased the likelihood of membership in the treatment-resistant class, odds ratios (ORs) = 1.12-1.53, 1.16-1.32, and 2.89, respectively. Additionally, participants in the treatment-resistant class had higher pretreatment PTSD scores for reexperiencing, avoidance, and hyperarousal symptoms, ORs = 5.24, 2.62, and 3.86, respectively. Findings suggest the importance of triaging individuals and offering interventions tailored to severity of presentation.

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

Background: Vascular cognitive impairment causes significant disability in the elderly and is common following ischaemic stroke. Although the underlying mechanisms and prognostic factors remain unclear, small vessel diseases are known to contribute. Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) manifestation of small vessel diseases and may contribute to vascular cognitive impairment, particularly frontal-executive functions. We hypothesized that baseline CMBs would predict long-term cognitive outcome, specifically frontal-executive function. Methods: A cohort of consecutive patients found to have CMBs when first referred to a stroke clinic, together with a CMB-free control group matched for age, gender and clinicoradiological characteristics, were invited for follow-up cognitive assessment a median of 5.7 years later. MRI and detailed cognitive assessment (including current intellectual function, verbal memory, visual memory, naming skills, perceptual functions, frontal-executive functions; and speed and attention) were performed at baseline and follow-up. Patients were classified (blinded to MRI and clinical data) as impaired or unimpaired in each domain using predefined criteria. We compared the prevalence of cognitive impairments in each domain at baseline and follow-up and investigated clinical and radiological predictors [including baseline CMBs and white matter changes (WMCs)] of frontal-executive cognitive impairment. Results: Of the original cohort of 55 patients, 13 died without follow-up. Twenty-six of the surviving patients (9 with, 17 without baseline CMBs) agreed to follow-up neuropsychological assessment; 21 of these patients had a repeat MRI scan. The median number of cognitive domains impaired increased, regardless of the presence of baseline CMBs (with baseline CMBs: median 3, range 0–5 at follow-up vs. median 2, range 0–2 at baseline, p = 0.016; without CMBs: median 1.0, range 0–5 at follow-up vs. median 0, range 0–5 at baseline, p = 0.035). Frontal-executive impairment at follow-up was more prevalent in patients with baseline CMBs than in those without (78 vs. 29%, p = 0.038). The presence of baseline CMBs predicted frontal-executive impairment at follow-up (OR 8.40, 95% CI 1.27–55.39, p = 0.027). Fifty percent of patients with CMBs versus 8% of patients without baseline CMBs developed new CMBs (p = 0.047). The severity of WMCs increased; the difference was statistically significant only in patients without baseline CMBs (p = 0.027). There were no new cortical infarcts. Conclusion: In stroke clinic patients, CMBs are consistently associated with frontal-executive impairment; baseline CMBs are associated with frontal-executive impairment at follow-up after 5.7 years. The presence of CMBs has prognostic relevance for long-term cognitive outcome in stroke clinic patients, and may help to optimally target preventive strategies in individuals at highest risk of cognitive decline.

Objectives Vascular cognitive impairment and Alzheimer9s disease (AD) may interact and co-exist. We investigated the prevalence and impact of mesial temporal lobe atrophy (MTA), a radiological marker for AD, in a population of stroke patients. Methods Patients referred to a stroke service underwent detailed neuropsychological testing and standardised imaging, including GRE T2* MRI and FLAIR. We assessed MTA on FLAIR images using a newly developed and validated visual rating scale based on the Scheltens scale (scores 0 to 4; mild MTA Findings 396 patients with full neuropsychological testing and complete MRI sequences were included (358 mild and 38 severe MTA). 171 patients (43%) showed some degree (score ≥1) of MTA. Patients with severe MTA were older (76 vs 64, p=0.000), more hypertensive (97% vs 66%, p=0.000), and had more severe WMC (median 9 vs 5.5, p=0.000) than patients with mild or no MTA. In adjusted multivariate analyses, MTA was a predictor of verbal memory impairment (OR 1.81, p=0.004) and frontal executive dysfunction (OR 1.48, p=0.023). Conclusions MTA is common in stroke patients and is independently associated with verbal memory and frontal executive deficits. Alzheimer pathology may play an important role in cognitive impairment in patients with cerebrovascular disease.

Methionine aminopeptidases (MetAP) are metalloenzymes that remove the N-terminal initiator methionine from newly synthesized polypeptides allowing essential post-translational modifications such as acetylation and myristoylation to take place. MetAP2, one of the two eukaryotic forms of the enzyme, was identified as the target of fumagillin, a natural product with anti-angiogenic properties that inhibits the proliferation of endothelial cells. Clinical activity has been seen for a semi-synthetic analogue of fumagillin, TNP470, suggesting MetAP2 is a good target for inhibiting angiogenesis. In vitro, MetAP2 appears to have sites for two divalent metal ions within its active site but there has been much discussion around the identity and number of metal ions actually present in the physiological states of the various MetAPs. An understanding of the physiologically relevant metalloform of the enzyme is essential for designing inhibitors that are active in cells. We have used tool compounds that bind the active site metals in diverse ways to investigate the relevance of the two potential metal binding sites in MetAP2. Using our fragment-based screening approach, Pyramid™, we screened the manganese-form of the MetAP2 enzyme. We identified multiple low-molecular weight fragment hits and confirmed their modes of binding to the two metals in the active site of MetAP2 by X-ray crystallography. Three hit series, which bound metal 1 only, metal 2 only or both metals 1 and 2 were chosen for further optimization using structure-based drug design. Optimized lead compounds had potent inhibitory activity against the in vitro MetAP2 enzyme (∼100 nM) and in HUVEC proliferation assays, whilst also showing greater than 1000-fold selectivity for MetAP2 over MetAP1. Examples from each series, representing different active site metal binding modes, were used as tool compounds to investigate the mechanism of action in cells. The levels of the MetAP2 substrate, 14-3-3, were monitored by western blot in HUVECs treated with these compounds. Levels of methionylated 14-3-3 increased upon treatment with compounds from each of our series indicating the substrate was not being processed and that in each case the compound was inhibiting MetAP2 in these cells. These data indicate that the physiological form of MetAP2 can be inhibited by compounds which bind solely to either of the two active-site metals, suggesting that both metals must be present in the intra-cellular form of MetAP2 and allowing multiple approaches to inhibiting this key angiogenic target. The lead series identified here provide chemically diverse scaffolds for further optimization of drug like properties. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A1.