A Latent Class Analysis on Symptoms of Prolonged Grief, Post-Traumatic Stress, and Depression Following the Loss of a Loved One

Background: The loss of a significant other can lead to variety of responses, including prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression. The aim of this study was to replicate and extend previous research that indicated that three subgroups of bereaved individuals can be distinguished based one similar post-loss symptom profiles using latent class analysis (LCA). The second aim was to examine whether sociodemographic and loss-related characteristics as well as the extent of meaning making were related to classes with more pervasive psychopathology. Methods: Telephone-based interviews with 433 Dutch and German speaking persons who had lost a significant other at last 6 months earlier were conducted. Self-rated PGD, PTSD, and depression symptoms were assessed. LCA was conducted and correlates of class-membership were examined using the 3step approach. Results: The LCA resulted in three distinct classes: a no symptoms class (47%), a moderate PGD, low depression/PTSD class (32%), and a high PGD, moderate depression/PTSD class (21%). A multivariate analysis indicated that female gender, a shorter time since loss, an unexpected loss and less meaning made to a loss were significantly associated with membership to the moderate PGD, low depression/PTSD and high PGD, moderate depression/PTSD class compared to membership to the no symptom class. Losing a child or spouse, a shorter time since loss, and having made less meaning to the loss further distinguished between the high PGD, moderate depression/PTSD symptom class and the moderate PGD, low depression/PTSD class. Discussion: We found that the majority of individuals coped well in response to their loss since the no symptom class was the largest class. Post-loss symptoms could be categorized into classes marked by different intensity of symptoms, rather than qualitatively different symptom patterns. The findings indicate that perceiving the loss as more unexpected, finding less meaning in the loss, and loss-related factors, such as the recentness of a loss and the loss of a partner or child, were related to class membership more consistently than sociodemographic factors

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma

BACKGROUND: Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS: Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT. RESULTS: We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUSIONS: These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells. FUNDING: NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation

Identification and characterization of a novel non-structural protein of bluetongue virus

Bluetongue virus (BTV) is the causative agent of a major disease of livestock (bluetongue). For over two decades, it has been widely accepted that the 10 segments of the dsRNA genome of BTV encode for 7 structural and 3 non-structural proteins. The non-structural proteins (NS1, NS2, NS3/NS3a) play different key roles during the viral replication cycle. In this study we show that BTV expresses a fourth non-structural protein (that we designated NS4) encoded by an open reading frame in segment 9 overlapping the open reading frame encoding VP6. NS4 is 77–79 amino acid residues in length and highly conserved among several BTV serotypes/strains. NS4 was expressed early post-infection and localized in the nucleoli of BTV infected cells. By reverse genetics, we showed that NS4 is dispensable for BTV replication in vitro, both in mammalian and insect cells, and does not affect viral virulence in murine models of bluetongue infection. Interestingly, NS4 conferred a replication advantage to BTV-8, but not to BTV-1, in cells in an interferon (IFN)-induced antiviral state. However, the BTV-1 NS4 conferred a replication advantage both to a BTV-8 reassortant containing the entire segment 9 of BTV-1 and to a BTV-8 mutant with the NS4 identical to the homologous BTV-1 protein. Collectively, this study suggests that NS4 plays an important role in virus-host interaction and is one of the mechanisms played, at least by BTV-8, to counteract the antiviral response of the host. In addition, the distinct nucleolar localization of NS4, being expressed by a virus that replicates exclusively in the cytoplasm, offers new avenues to investigate the multiple roles played by the nucleolus in the biology of the cell

OAS1 Polymorphisms Are Associated with Susceptibility to West Nile Encephalitis in Horses

West Nile virus, first identified within the United States in 1999, has since spread across the continental states and infected birds, humans and domestic animals, resulting in numerous deaths. Previous studies in mice identified the Oas1b gene, a member of the OAS/RNASEL innate immune system, as a determining factor for resistance to West Nile virus (WNV) infection. A recent case-control association study described mutations of human OAS1 associated with clinical susceptibility to WNV infection. Similar studies in horses, a particularly susceptible species, have been lacking, in part, because of the difficulty in collecting populations sufficiently homogenous in their infection and disease states. The equine OAS gene cluster most closely resembles the human cluster, with single copies of OAS1, OAS3 and OAS2 in the same orientation. With naturally occurring susceptible and resistant sub-populations to lethal West Nile encephalitis, we undertook a case-control association study to investigate whether, similar to humans (OAS1) and mice (Oas1b), equine OAS1 plays a role in resistance to severe WNV infection. We identified naturally occurring single nucleotide mutations in equine (Equus caballus) OAS1 and RNASEL genes and, using Fisher's Exact test, we provide evidence that mutations in equine OAS1 contribute to host susceptibility. Virtually all of the associated OAS1 polymorphisms were located within the interferon-inducible promoter, suggesting that differences in OAS1 gene expression may determine the host's ability to resist clinical manifestations associated with WNV infection

Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

Traumatic grief after disasters worldwide

Experiencing the death of a significant other due to a disaster heightens the risk of disturbed grief with comorbid posttraumatic stress disorder (PTSD) and depression, also referred to as traumatic grief. The present symposium seeks to elucidate the patterns of traumatic grief symptoms following loss in major disasters in over 1500 disaster-bereaved people. First, the results of two latent class analyses on traumatic grief symptoms among Sichuan earthquake survivors and internally displaced Colombians will be discussed. Analyses show that traumatic grief, disturbed grief and/or PTSD symptom classes can be distinguished in disasterbereaved people. Next, two four-wave longitudinal studies will be presented on people bereaved through the Utøya terrorist attack and the MH17 airplane disaster. Results indicate that the course and aetiology of disturbed grief differs from PTSD and depression. Clinical implications of findings and cultural considerations will be discussed