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Background and objectives: Eye movement desensitization and reprocessing (EMDR) is an effective treatment for individuals suffering from posttraumatic stress disorder (PTSD). However, EMDR is not typically offered to people with PTSD who also meet the criteria for borderline personality disorder (BPD). This study examines the feasibility and clinical benefits of EMDR for PTSD delivered in addition to the onset of treatment as usual (TAU) for BPD. Methods: In a non-concurrent, multiple baseline design, 12 patients with BPD and PTSD received fifteen weekly 45-min sessions of TAU. During this period, eight weekly 90-min EMDR sessions were added. Outcome measures were obtained weekly for self-reported PTSD symptoms (PTSD checklist for DSM-5), levels of psychopathology (Brief Symptom Checklist), and the effect of psychopathology on different areas of life (Sheehan Disability Scale). Results: 9 participants completed the treatment protocol. In the EMDR phase, PTSD severity scores decreased significantly between sessions, while no between-session drop in scores occurred during the TAU only phase. Similar results were obtained for general symptoms and disability. No adverse events were reported. Limitations: Results on the efficacy and safety of EMDR in patients with BPD and PTSD need to be replicated in larger samples and in RCTs before they can be generalized to the entire population. Conclusions: The results of our study suggest that EMDR may be feasible and effective in reducing PTSD symptoms in patients concurrently receiving BPD treatment. EMDR appears to be a promising intervention for patients with BPD and comorbid PTSD.

Background: The clinical staging model states that psychosis develops through subsequent stages of illness severity. To better understand what drives illness progression, more extensive comparison across clinical stages is needed. The current paper presents an in-depth characterization of individuals with different levels of risk for psychosis (i.e., different early clinical stages), using a multimethod approach of cross-sectional assessments and daily diary reports.Methods: Data came from the Mirorr study that includes N = 96 individuals, divided across four subgroups (n1 = 25, n2 = 27, n3 = 24, and n4 = 20). These subgroups, each with an increasing risk for psychosis, represent clinical stages 0-1b. Cross-sectional data and 90-day daily diary data on psychopathology, well-being, psychosocial functioning, risk and protective factors were statistically compared across subgroups (stages) and descriptively compared across domains and assessment methods.Results: Psychopathology increased across subgroups, although not always linearly and nuanced differences were seen between assessment methods. Well-being and functioning differed mostly between subgroup 1 and the other subgroups, suggesting differences between non-clinical and clinical populations. Risk and protective factors differed mostly between the two highest and lowest subgroups, especially regarding need of social support and coping, suggesting differences between those with and without substantial psychotic experiences. Subgroup 4 (stage 1b) reported especially high levels of daily positive and negative psychotic experiences.Conclusions: Risk for psychosis exists in larger contexts of mental health and factors of risk and protection that differ across stages and assessment methods. Taking a broad, multi-method approach is an important next step to understand the complex development of youth mental health problems.

Objective Comprehensive and reliable genome-wide variant analysis of a small number of cells has been challenging due to genome coverage bias, PCR over-cycling, and the requirement of expensive technologies. To comprehensively identify genome alterations in single colon crypts that reflect genome heterogeneity of stem cells, we developed a method to construct whole-genome sequencing libraries from single colon crypts without DNA extraction, whole-genome amplification, or increased PCR enrichment cycles. Results We present post-alignment statistics of 81 single-crypts (each contains four- to eight-fold less DNA than the requirement of conventional methods) and 16 bulk-tissue libraries to demonstrate the consistent success in obtaining reliable coverage, both in depth (≥ 30X) and breadth (≥ 92% of the genome covered at ≥ 10X depth), of the human genome. These single-crypt libraries are of comparable quality as libraries generated with the conventional method using high quality and quantities of purified DNA. Conceivably, our method can be applied to small biopsy samples from many tissues and can be combined with single cell targeted sequencing to comprehensively profile cancer genomes and their evolution. The broad potential application of this method offers expanded possibilities in cost-effectively examining genome heterogeneity in small numbers of cells at high resolution.

PDF file - 157K, Supplemental Table 1. Regulatory T cell genes included in this study (N=25). Supplemental Table 2. Regulatory T cell SNPs included in this study. Supplemental Table 3. Participating invasive epithelial ovarian cancer studies. Supplemental Table 4. Association between clinical variables and overall survival.

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.Results: The five polymorphisms were not associated with ovarian carcinoma overall (Ptrend > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; Pheterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).Conclusions: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.Impact: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Cancer Epidemiol Biomarkers Prev; 19(7); 1822–30. ©2010 AACR.

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Supplementary Tables 1-2 from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium

PDF - 149K, Supplemental Table 1. Participating invasive epithelial ovarian cancer studies. Supplementary Table 2. NF-κB genes studied. Supplemental Table 3. Association between clinical variables and overall survival.

Supplementary Table 4 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Association between CCNE1 variants and bladder cancer

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Supplementary Figure 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

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Supplementary Table 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Supplementary Table 3 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Supplementary Figure 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

PDF file - 145K, Supplementary Table 1. Studies in the Ovarian Cancer Association Consortium (OCAC) are listed, as well as the abbreviation, location, type, and number of cases and controls for each study. Supplementary Table 2. The number of cases included in the analysis from each OCAC study site is listed by histologic subtype. Supplementary Table 3. Gene symbols and IDs are listed for NF-κB pathway genes that were tagged in this study, as well as chromosome position, number of SNPs tagged, and bin coverage of each gene using Hapmap or 1000 genomes as a reference. Supplementary Table 4. Reasons and numbers of samples excluded from the analysis following the sample quality control are described. Supplementary Table 5. We evaluated rs17561 and rs6785617 for interactions with known epidemiologic risk factors for risk of clear cell and LMP tumors, respectively, and report interaction p-values in the table below.

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]

Supplementary Table 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer. Cancer Res; 72(3); 707–15. ©2011 AACR.

Supplementary Figure 1: Electrophoretic mobility shift assays (EMSA) for CCNE1 SNPs rs8102137 and rs7257330. Supplementary Figure 2: Alignment of cyclin E protein isoforms - WT1, WT2 and ES and ET. Supplementary Figure 3: Functional analysis of cyclin E isoforms.Supplementary Table 1: Description of sub-studies included in NCI-GWAS1 and GWAS2 of bladder cancer. Supplementary Table 2: Characteristics of bladder tissue samples used for mRNA expression analysis. Supplementary Table 3: PCR primers, genotyping and gene expression assays, EMSA probes and antibodies. Supplementary Table 4: Bladder cancer stage and grade information for patients in the combined GWAS1+2 set. Supplementary Table 6: Association with bladder cancer risk with mutual adjustment for CCNE1 variants. Supplementary Table 7: Association with bladder cancer risk for CCNE1 variants previously associated with other cancers and for two non-synonymous coding variants. Supplementary Table 8: Association between cyclin E protein expression (IHC scores), bladder cancer patient characteristics and CCNE1 variants.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Background: Studies show that the trauma-sensitivity of professionals working with patients with psychosis is insufficient. As a result, trauma-related problems remain undetected and untreated, which may impede recovery in this group. This study explored the effects of a specialised staff training on six trauma-sensitivity factors (i.e. knowledge, credibility, expected burden, harm expectancy, diagnostic competency and organizational support), self-reported trauma-sensitive behaviour and objective indicators of trauma-sensitive behaviour in medical files. Method: Professionals (N = 56) rated the six trauma-sensitivity factors and their own trauma-sensitive behaviour at pre-training, post-training and at 6- and 12-months follow-up. Changes in indicators of trauma-sensitive behaviours were assessed by a review of medical files (N = 97). Results: The specialized training increased knowledge, crediblity and experienced diagnostic compentence. The training decreased burden and harm expectancies, and enhanced self-reported trauma-sensitive behaviour. However, this positive change could not be objectified by indicators of trauma-sensitive behaviour in medical files. Discussion: These findings support the notion that specialised training has a positive effect on increasing trauma-sensitivity and decreasing burden and harm expectancies, but not necessarily on observable trauma-sensitive behaviour. In addition to training staff, structural implementation and organisational support are argued to be essential to attain actual behaviour change.

ObjectiveThe objective of this study was to gain insight into patients' experiences of how personal recovery (PR) is facilitated or hindered in the context of an early episode psychosis setting (Soteria). We thereby aimed to contribute to the understanding of how care settings may promote or hinder the process of PR in people with (acute) psychosis.MethodThis study used a qualitative method, consisting of semi-structured in-depth interviews with people who had been admitted to a Soteria house in the Netherlands. Interview transcripts were analyzed following the Grounded Theory approach.ResultsFive themes emerged from the data illustrating how Soteria facilitated or impeded PR. The experience of togetherness in contact with staff and peers, feeling at home, and being active facilitated PR, while the emphasis put on medication by staff was experienced as hindering, and attention to spirituality was missed.ConclusionIn addition to the literature that identified factors associated with PR in psychosis, the current study gives a sense of how this can be put into practice. By offering treatment within a normalizing, holding environment, with emphasis on equality, close contact, optimism, active structured days, open-mindedness toward spirituality, and the role of medication, PR can be facilitated without detracting from guideline-based treatment aimed at symptomatic recovery. Similarities with existing concepts are discussed.

Background: Temstem is a mobile application developed in cooperation with voice-hearing persons to help them cope with distressing voices. After psychoeducation about voice hearing, Temstem offers two functions: Silencing is a mode designed to inhibit voice activity through the processing of incompatible language; the Challenging mode introduces dual tasking (as used in eye movement desensitisation and reprocessing) designed to reduce the emotionality and vividness of a voice memory. Two different language games, Lingo Tapper and Word Link, are provided, containing both functions. This study aimed to explore the momentary effects of Temstem on voice-hearing distress, emotionality and vividness in a naturalistic sample of voice-hearing app users. Method: Temstem is freely available in the Netherlands. We collected data through the app from 1048 individual users who had given informed consent for the study. We assessed changes in pre- and post-session scores on distress, emotionality and vividness, and we evaluated differences in outcomes between the games and whether effects remained stable over multiple sessions. Results: Users had been hearing voices for an average of 4.95 years; 79 % had been informed about Temstem by a mental health therapist or coach. After a Silencing session, voice-hearing distress was reduced, t(958) = 27.12, p < .001, d = 0.49; the degree of reduction remained stable after repeated use, F(1, 7905.57) = 1.91, p = .167. After a Challenging session, emotionality, t(651) = 23.16, p < .001, d = 0.74, and the vividness of voice memories were reduced, t(651) = 22.20, p < .001, d = 0.71; both diminished slightly with frequent use, F(1, 2222.86) = 7.21, p < .05; F(1, 2289.92) = 4.25, p < .05. In comparison with Lingo Tapper, larger reductions were seen for a Word Link game: emotionality t(226) = 2.88, p < .005, d = 0.21; vividness t(226) = 2.29, p < .05, d = 0.17. Discussion: In this heterogeneous sample of voice-hearing individuals, Temstem appeared to be a promising coping tool; momentary voice-hearing distress and the emotionality and vividness of voice statements were reduced after a Temstem session. Despite important limitations and the need for more research, naturalistic studies of user app data may yield interesting and generalisable findings.

BackgroundUnderstanding the interplay between trauma-related psychological mechanisms and psychotic symptoms may improve the effectiveness of interventions for post-traumatic stress reactions in psychosis. Network theory assumes that mental health problems persist not because of a common latent variable, but from dynamic feedback loops between symptoms, thereby addressing the heterogeneous and overlapping nature of traumagenic and psychotic diagnoses. This is a proof-of-concept study examining interactions between post-traumatic stress symptoms, which were hypothesized to reflect trauma-related psychological mechanisms, and auditory hallucinations and delusions.MethodBaseline data from two randomised controlled trials (N = 216) of trauma-focused therapy in people with post-traumatic stress symptoms (87.5% met diagnostic criteria for PTSD) and psychotic disorder were analysed. Reexperiencing, hyperarousal, avoidance, trauma-related beliefs, auditory hallucinations and delusional beliefs were used to estimate a Gaussian graphical model along with expected node influence and predictability (proportion of explained variance).ResultsTrauma-related beliefs had the largest direct influence on the network and, together with hypervigilance, were implicated in the shortest paths from flashbacks to delusions and auditory hallucinations.ConclusionsThese findings are in contrast to previous research suggesting a central role for re-experiencing, emotional numbing and interpersonal avoidance in psychosis. Trauma-related beliefs were the psychological mechanism most associated with psychotic symptoms, although not all relevant mechanisms were measured. This work demonstrates that investigating multiple putative mediators may clarify which processes are most relevant to trauma-related psychosis. Further research should use network modelling to investigate how the spectrum of traumatic stress reactions play a role in psychotic symptoms.

Introduction Many people with psychotic disorders experience symptoms of post-traumatic stress disorder (PTSD). In recent years, several trauma-focused therapies (TFTs), including cognitive restructuring (CR), prolonged exposure (PE), and eye movement desensitization and reprocessing (EMDR) have been studied and found to be safe and effective in reducing PTSD symptoms in individuals with psychosis. However, studies were conducted in different countries, with varying inclusion criteria, therapy duration, control groups, and trial outcomes. RE.PROCESS will be the first study to compare the impact of CR, PE, and EMDR with a waiting list control condition within the same context. Methods and analysis This is the protocol of a pragmatic, single-blind, multicentre, superiority randomized controlled trial, in which CR, PE, and EMDR are compared to a waiting list control condition for TFT (WL) in a naturalistic treatment setting. Inclusion criteria are as follows: age ≥ 16 years; meeting full DSM-5 diagnostic criteria for PTSD on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), with a total CAPS score ≥ 23; and a psychotic disorder in the schizophrenia spectrum confirmed by the Structured Clinical Interview for DSM-5 (SCID-5). Participants (N=200) will be randomly allocated to 16 sessions of one of the TFTs or WL, in addition to receiving treatment as usual (TAU) for psychosis. The primary objective is to compare the effects of CR, PE, and EMDR to WL on researcher-rated severity of PTSD symptoms over time from baseline to 6-month follow-up. Secondary objectives are to examine these effects at the separate time-points (i.e., mid-treatment, post-treatment, and at 6-month follow-up) and to test the effects for clinician-rated presence of PTSD diagnosis, and self-rated severity of (complex) PTSD symptoms. Discussion This is the first RCT to directly compare the effects of CR, PE, and EMDR within the same context to TAU on PTSD symptoms in individuals with psychosis and PTSD. Secondary effects on clinical and functional outcomes will be investigated both directly after therapy and long term. Trial registration ISRCTN ISRCTN56150327. Registered 18 June 2019.

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis (MESA) which included several hundred individuals with whole genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, ten years apart. We evaluated each multi-omic phenotype’s ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62x and rare frameshift variants 216x as frequently as controls, compared to 13x to 27x for expression or protein effects alone. We developed a Bayesian hierarchical model to prioritize specific rare variants underlying multi-omic signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer’s disease.

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57–67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P

Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce Multi-set Correlation and Factor Analysis, an unsupervised integration method that enables fast inference of shared and private factors in multi-modal data. Applied to 614 ancestry-diverse participant samples across five ‘omics types, MCFA infers a shared space that captures clinically relevant molecular processes.

Background:Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD.Methods:Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE−/−) mouse model of atherosclerosis.Results:A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women’s Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.Conclusions:Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Background Post-traumatic mechanisms are theorised to contribute to voice-hearing in people with psychosis and a history of trauma. Phenomenological links between trauma and voices support this hypothesis, as they suggest post-traumatic processes contribute to the content of, and relationships with, voices. However, research has included small samples and lacked theory-based comprehensive assessments. Method In people with distressing voices (n = 73) who experienced trauma prior to voice-hearing, trauma–voice links were assessed both independently and dependently (descriptions were presented and rated separately and together, respectively) by both participants and researchers. A structured coding frame assessed four types of independent links (i.e. victimisation type, physiological-behavioural, emotional, and cognitive response themes including negative self-beliefs) and three types of dependent links: relational (similar interaction with/response to, voice and trauma); content (voice and trauma content are exactly the same); and identity (voice identity is the same as perpetrator). Results Independent links were prevalent in participants (51–58%) and low to moderately present in researcher ratings (8–41%) for significant themes. Identification of negative self-beliefs in trauma was associated with a significantly higher likelihood of negative self-beliefs in voices [participants odds ratio (OR) 9.8; researchers OR 4.9]. Participants and researchers also reported many dependent links (80%, 66%, respectively), most frequently relational links (75%, 64%), followed by content (60%, 25%) and identity links (51%, 22%). Conclusion Trauma appears to be a strong shaping force for voice content and its psychological impact. The most common trauma–voice links involved the experience of cognitive-affective psychological threat, embodied in relational experiences. Trauma-induced mechanisms may be important intervention targets.

Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n=183), Chinese (n=71), European (n=416), and Hispanic/Latino (n=301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ~50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods athttps://doi.org/10.5281/zenodo.4837328.Author summaryGene regulation is a critical mechanism underlying complex traits. Transcriptome-wide association studies (TWAS) have helped elucidate potential mechanisms because each association connects a gene rather than a variant to the complex trait. Like genome-wide association studies (GWAS), most TWAS are still conducted exclusively in populations of European ancestry, which misses the opportunity to test the full spectrum of human genetic variation for associations with complex traits. Here, move beyond the transcriptome and because protein measurement assays are growing to allow interrogation of the proteome, we use data from TOPMed MESA to develop genetic predictors of protein abundance in diverse ancestry populations. We compare model-building strategies with the goal of providing the best resource for protein association discovery with available data. We demonstrate how these prediction models can be used to perform proteome-wide association studies (PWAS) in diverse populations. We show the most protein-trait associations were discovered, colocalized, and replicated in independent cohorts using proteome prediction model training populations with similar ancestries to individuals in the GWAS. We shared our protein prediction models and performance statistics publicly to facilitate future proteome mapping studies in diverse populations.

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Background Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.

Background Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorder, but psychological help remains difficult to access and accept for youth, calling for novel, youth-friendly approaches. Mobile Health (mHealth) and, most prominently, ecological momentary interventions (EMIs) provide a unique opportunity to deliver youth-friendly, personalized, real-time, guided self-help interventions. The aim of this study is to investigate the efficacy of a novel, accessible, transdiagnostic ecological momentary intervention for improving self-esteem (‘SELFIE’) in youth with prior exposure to childhood adversity. Methods/design In a parallel-group, assessor-blind, multi-center randomized controlled trial, individuals aged 12–26 years with prior exposure to childhood adversity and low self-esteem will be randomly allocated to SELFIE in addition to treatment as usual (TAU) as the experimental condition or the control condition of TAU only, which will include access to all standard health care. SELFIE is a digital guided self-help intervention administered through a smartphone-based app to allow for interactive, personalized, real-time and real-world transfer of intervention components in individuals’ daily lives, blended with three training sessions delivered by trained mental health professionals over a 6-week period. Outcomes will be assessed at baseline, post-intervention, and 6-month follow-up by blinded assessors. The primary outcome will be the level of self-esteem as measured with the Rosenberg Self-Esteem Scale (RSES). Discussion The current study is the first to establish the efficacy of an EMI focusing on improving self-esteem transdiagnostically in youth exposed to childhood adversity. If this trial provides evidence on the efficacy of SELFIE, it has significant potential to contribute to minimizing the deleterious impact of childhood adversity and, thereby, preventing the development of mental disorder later in life. Trial registration Netherlands Trial Register NL7129 (NTR7475). Registered on 9 November 2018

Despite empirical evidence for multifactorial causes of voice-hearing, people's own beliefs about what caused their voices are understudied. People with distressing voices (n=125) completed measures of trauma, post-traumatic stress disorder (PTSD) symptoms, and beliefs about causality. Most participants reported trauma in the past (97%) and PTSD symptoms were prevalent. Traumatic experiences were the most commonly endorsed causal factor of voice-hearing (64%), followed by distress (62%). Beliefs about biological causes, including drug use (22%), were least endorsed. Those who experienced more traumatic events and more PTSD symptoms were more likely to endorse trauma as a causal factor of voice-hearing (R2=0.38).

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2–4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan–Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50%, with and without chr17p CNLOH, p = 0.0002), and chr13q in patients not in CR (3-year OS = 4% vs. 26%, with and without chr13q CNLOH, p

The role of common variants in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. These diseases may have a shared molecular basis and identifying germline loci associated with the risk for their development could be important. We performed AML and MDS genome-wide association studies (GWAS) in European Americans from the DISCOVeRY-BMT study population (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). We identified an increased risk for de novo AML and MDS (OR=1.38, 95% CI, 1.26-1.51, P meta =2.8×10 −12 ) in patients carrying the T allele at rs12203592 in Interferon Regulatory Factor 4 ( IRF4 ), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Variants in this gene are recognized to confer increased susceptibility to B-cell malignancies. Rs12203592 is

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Background: Donor-derived T cells that target minor histocompatibility antigens (mHAs) in allogeneic hematopoietic cell transplant (HCT) mediate graft versus leukemia (GvL) and graft versus host (GvH) effects. Prediction of mHAs that drive GvL has garnered interest for targeted immunotherapy, but there have been few large-scale studies of population prevalence of predicted mHAs. Prioritization of mHAs that are shared among patients would allow for treatment of more individuals with mHA-targeting therapies. We report here population metrics of predicted mHAs in a dataset of over 3000 patients treated with HCT and reported to CIBMTR from 2000-2011. Our goal is to identify the most common mHAs within leukemia and Myelodysplastic Syndrome (MDS) patient populations to target with T cell immunotherapies or graft engineering techniques. Methods: Data is derived from two cohorts of donor recipient HCT pairs (DRPs) treated for Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), and MDS from the CIBMTR and previously analyzed in DISCOVeRY-BMT. Cohort 1 included 2609 10/10 HLA-matched DRPs treated from 2000-2008, and Cohort 2 included 572 10/10 HLA-matched DRPs treated from 2009-2011 plus 351 8/8 HLA-matched DRPs treated from 2000-2011 (Hahn et al. 2015, Biol Blood Marrow Transplant). Cohorts were combined for analyses. Approximately 20,000 missense SNPs were extracted from Illumina HumanOmni Express genotyping data. Computational mHA prediction was performed according to prior work from our lab (Lansford et al. 2018, Blood Adv.). Minor mismatches were predicted based on coding SNPs present in the recipient but not donor. mHAs were defined as mismatches that would lead to variant peptides predicted to bind at least 1 recipient HLA molecule and be expressed in leukemia cells (GvL mHA) and/or acute GvHD target organs (GvH mHA). GvL mHAs were categorized as "GvL,No_GvH" or "GvL" based on transcripts per million (TPM) corresponding to GvH organs, with "GvL" indicating between 5-50 TPM and "GvL,No_GvH" indicating Results: Patient demographics and number of total predicted mHAs from each ethnic group are shown in Table 1. Number of predicted mHAs per patient varied widely both within and between HLA types (Figure 1). Despite underrepresentation of some ethnic groups in our dataset, we identified thousands of potential mHAs in each group (Figure 2A). GvL mHA and GvH mHA proportions were similar across recipient ethnicities (Figure 2A-B). GvL mHA made up approximately half of predicted mHAs for each ethnic group (Figure 2B). Total numbers of mHAs per HCT recipient were significantly different between recipient ethnic groups within each cohort (Figure 2C). Although proportions of GvL vs GvH mHAs were stable across HLA alleles, there were substantial differences in number of predicted mHA by allele (Figure 3). Despite limited representation of some HLA types in our dataset, we were able to identify GvL mHAs for potential therapeutic targeting corresponding to 56 HLA alleles. We generated ranked lists of the most common shared mHA for each HLA allele, using an implementation of the standard greedy algorithm solution to the maximum set coverage problem. With this method, we identified the fewest number of mHA peptides needed to cover desired percentages of the recipient population with at least one mHA. For example, for HLA A*02:01, HLA*B07:02, and HLA*C07:01, engineering T cells to target the top nine to twelve peptides would allow for treatment of 80% of the patient population in our cohorts (Figure 4). These represent common HLA alleles in Caucasian, African American, Hispanic, and Asian populations, indicating that this technique can identify targets that could be therapeutically beneficial for a greater diversity of patients than standard treatments. mHA pools can also be filtered on peptide expression or HLA binding to ensure that the targeted peptides are highly expressed and presented. Conclusions: Despite differences in predicted number of mHA by ethnicity and HLA alleles, shared GvL mHA exist across common HLA. To the extent that these are targetable by adoptive cellular therapy, we can expand equal access to mHA targeted immunotherapies, improving upon traditional models where only the most prevalent HLA types are covered. Disclosures Armistead: Cell Microsystems: Patents & Royalties: Patent application U.S. 16/347,104 "Automated collection of a specified number of cells"; GeneCentric: Consultancy. Vincent:GeneCentric Therapeutics: Consultancy.

Contains fulltext : 213542.pdf (Publisher’s version ) (Closed access) It has only been in this last decade that trauma-focused treatments (TFT) have been studied in patients with psychotic disorders. Before, the paradigm stated that TFT was contraindicated in these patients because clinicians and researchers assumed the risk of exacerbation of symptoms was too high. The purpose of this article is to examine the effectiveness of eye movement desensitization and reprocessing (EMDR) therapy in the treatment of psychosis. To this end, we will present a brief narrative review of the current state of research in this particular field. The results suggest that, contrary to the "no-TFT-in-psychosis" paradigm, TFTs such as EMDR therapy can successfully be used to reduce trauma-related symptoms in patients with psychosis. Moreover, there are now provisional indications that psychotic symptoms such as delusions and hallucinations can be targeted directly and indirectly using EMDR therapy. 12 p.

TO THE EDITOR: In their recent report in Blood Advances , Martinez-Laperche et al[1][1] proposed a predictive model for the risk of acute and chronic graft-versus-host disease (GVHD) based on the selection of clinical variables and 25 single-nucleotide polymorphisms (SNPs), spanning different

The field of digital mental health is rapidly expanding with digital tools being used in assessment, intervention, and supporting self-help. The application of digital mental health to hallucinations is, however, at a very early stage. This report from a working group of the International Consortium on Hallucinations Research considers particular synergies between the phenomenon of hallucinations and digital tools that are being developed. Highlighted uses include monitoring and managing intermittently occurring hallucinations in daily life; therapeutic applications of audio and video media including virtual and augmented reality; targeting verbal aspects of hallucinations; and using avatars to represent hallucinatory voices. Although there is a well-established Internet-based peer support network, digital resources for hallucinations have yet to be implemented in routine practice. Implementation may benefit from identifying how to market resources to the broad range of populations who experience hallucinations and identifying sustainable funding models. It is envisaged that digital tools will contribute to improved self-management and service provision for people experiencing hallucinations. Keywords: digital mental health, mHealth, Internet, smartphones, hearing voices, schizophrenia publishedVersion