Group schema therapy for personality disorders: Systematic review, research agenda and treatment implications.

OBJECTIVE: There are significant temporal and financial barriers for individuals with personality disorders (PD) receiving evidence-based psychological treatments. Emerging research indicates Group Schema Therapy (GST) may be an accessible, efficient, and cost-effective PD intervention, however, there has been no synthesis of the available evidence to date. This review therefore aimed to investigate the efficacy of GST for PDs by systematically synthesizing available literature. METHOD: Five electronic databases were screened with resulting studies subjected to a specific eligibility criteria, which yielded fourteen relevant studies. Characteristics were extracted and methodological quality rigorously assessed. RESULTS: Strong support was evidenced for GST's ability to reduce Cluster B and C symptomology, particularly for Borderline and Avoidant PD. GST appeared to improve global symptom severity, quality of life and functional capacity, as well as treatment targets such as schemas and modes. CONCLUSION: Although not without limitations and a moderate risk of bias, the current body of evidence supports GST as a potential solution to current service deficits in economical and evidence-based care for individuals with PD. Implications for treatment and future research are discussed.

An exploratory investigation of schema modes in social anxiety disorder: Empirical findings and case conceptualization.

BACKGROUND: Current "gold standard" treatments for social anxiety disorder (SAD) are limited by the limited emphasis of key etiological factors in conceptualization, and many individuals with SAD experience residual symptoms posttreatment. Hence, the novel application of the Schema Therapy Mode Model may provide a helpful framework for extending clinical understanding and treatment options for SAD. This exploratory study aimed to investigate the presence and pattern of schema modes among SAD individuals. METHOD: Forty individuals with SAD completed questionnaire measures of symptomatology, social anxiety-relevant cognitions, schema modes, childhood trauma, and parental style. RESULTS: Key maladaptive schema modes identified in SAD were Vulnerable Child, Punitive Critic, Demanding Critic, Compliant Surrender, and Detached Self-Soother. CONCLUSION: Outcomes provide the basis for a proposed schema mode case conceptualization for SAD and are hoped to provide a rationale for testing the applicability of Schema Therapy as a novel treatment for SAD. Key limitations are discussed.

Severe acute hepatitis of unknown aetiology in children-what is known?

The ongoing investigations into clusters of children affected by severe acute hepatitis of unknown aetiology have put our global capacity for a coordinated, effective response to the test. The global health community have rapidly convened to share data and inform the response. In the UK, where most cases were initially identified, a coordinated public health and clinical research response was rapidly initiated. Since then, cases have been reported from other countries, predominantly from higher-income countries. While agencies are keeping an open mind to the cause, the working hypothesis and case notifications raise important questions about our capacity to detect emerging cases in lower-resourced settings with a recognised lack of access to diagnostics even for commonly circulating viruses such as hepatitis A. The limited capability to generate integrated global pathogen surveillance data is a challenge for the outbreak investigations, highlighting an urgent need to strengthen access to diagnostics, with a focus on lower-resourced settings, to improve the capacity to detect emerging diseases to inform care and to improve outcomes and outbreak control.

Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants.

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

Relapse of Aplastic Anemia with Majority Donor Chimerism (Donor-Type Aplasia) Occurring Late after Bone Marrow Transplantation.

There have been sporadic reports of the development of delayed disease recurrence after bone marrow transplantation for severe aplastic anemia despite sustained majority or full donor chimerism. This is termed "donor-type aplasia" (DTA). We describe the management and outcome of 11 pediatric patients from 8 institutions in Europe, the United States, and the Middle East who developed DTA at a mean of 35 months post-transplant. These patients were initially transplanted at a mean age of 10.0 years (range, 5.8 to 16.0 years), 9 from matched sibling donors and 2 from matched unrelated donors. Attempts to treat DTA with varying combinations of additional immunosuppression (including intravenous immunoglobulin, donor lymphocyte infusions, stem cell boosts, and other therapies) failed. Ten patients have received a conditioned second transplant, 9 from the same donor and 1 from a new matched unrelated donor. Aplasia has resolved in the remaining patient in response to ongoing eltrombopag therapy. All patients were alive at a mean of 92 months (range, 26 to 195) after a second transplant; 6 are in complete remission, but 4 suffered from second/recurrent DTA at 16 to 129 months after retransplant and required further transplant therapy.

Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion.

Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).

Experiential Self-Focus in Social Anxiety Disorder: Is it Beneficial?

OBJECTIVE: Self-focused processing is a significant maintaining factor in cognitive models of social anxiety disorder (SAD), but it may also be analytic (detached, evaluative, maladaptive) or experiential (concrete, nonevaluative, adaptive). The current study aimed to investigate the effect of self-focus modes in a sample meeting criteria for SAD as previous studies have yielded mixed results. METHOD: Individuals meeting criteria for SAD and nonanxious controls (N = 80, 77.5% female; mean age = 19.46) were randomly allocated to complete a task inducing analytic or experiential self-focused processing, followed by a social interaction task, including measurement of affective and cognitive variables. RESULTS: Controls demonstrated the expected benefits of experiential compared to analytic self-focus on social anxiety, negative affect, and self-beliefs. Unexpectedly, SAD participants reported no difference between self-focus conditions. CONCLUSION: Results suggest that experiential processing may have no benefit for SAD individuals proximal to a social threat. Implications of these findings are discussed.

Bridging the Gap between Aetiological and Maintaining Factors in Social Anxiety Disorder: The Impact of Socially Traumatic Experiences on Beliefs, Imagery and Symptomatology.

BACKGROUND: A number of key environmental factors during childhood have been implicated in the aetiology of social anxiety disorder (SAD), including aversive social experiences, traumatic life events and parent-child interaction. However, understanding the nature, interactions and relative contributions of these factors remains unclear. Furthermore, the relation of aversive social experiences to the development of key maintaining factors in SAD requires elucidation. AIMS: The current study aimed to extend previous research regarding the aetiology of SAD by investigating the relationship between key environmental factors in childhood, negative beliefs and self-imagery, and the development of SAD. METHOD: Social anxiety disorder individuals (n = 40, 87.5% female, Mage = 20.25 years) completed self-report measures of social anxiety symptomatology, traumatic experiences and parenting style. In addition, participants were administered interviews assessing various domains of childhood trauma, as well as negative self-imagery and associated socially traumatic memories. RESULTS: Participants reported a high frequency of early traumatic experiences across all domains (physical, emotional, sexual, social and non-relational), as well as a high degree of parental overcontrol. However, social anxiety symptomatology was most strongly correlated with socially traumatic experiences, and mediation analyses suggest that appraisal of aversive social/peer experiences accounts for the relationship of SAD symptomatology with negative self-beliefs and imagery. CONCLUSIONS: These outcomes suggest that social trauma may be a key proximal cause of SAD development, leading to the development of negative beliefs and imagery that subsequently maintain the disorder. These findings have implications for understanding SAD aetiology, and improving treatment outcomes for the disorder. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGES: Negative social experiences have been implicated in the development of social anxiety disorder (SAD), but the role of this predisposing factor remains unclear. Compared with other risk factors for SAD, social anxiety symptomatology was most strongly correlated with socially traumatic experiences. Mediation analyses suggested that appraisal of aversive social experiences accounted for the relationship of SAD symptomatology with negative self-beliefs and imagery. These outcomes suggest that SAD individuals would benefit from interventions targeted at processing socially traumatic memories (e.g., imagery rescripting).

Characterization of leukemias with ETV6-ABL1 fusion.

To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.

Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.

A systematic review of mindfulness and acceptance-based treatments for social anxiety disorder.

CONTEXT: The cultivation of mindfulness and acceptance has been theoretically and empirically associated with psychological ancillary well-being and has demonstrated efficacy in the treatment of various disorders. Hence, mindfulness and acceptance-based treatments (MABTs) have recently been explored for the treatment of social anxiety disorder (SAD). This review aims to evaluate the benefits of MABTs for SAD. METHODS: Systematic review of studies investigating an MABT for individuals with SAD, using PsycInfo, Medline, PubMed, and Cochrane Central Register of Controlled Trials. RESULTS: Nine studies were identified. Significant improvements in symptomatology were demonstrated following the MABT, but benefits were equivalent or less than yielded by cognitive-behavioral therapy (CBT). LIMITATIONS: The few treatment studies available were compromised by significant methodological weaknesses and high risk of bias across domains. Studies were largely uncontrolled with small sample sizes. The hybrid nature of these interventions creates ambiguity regarding the specific utility of treatment components or combinations. CONCLUSIONS: MABTs demonstrate significant benefits for reducing SAD symptomatology; however, outcomes should be interpreted with caution until appropriate further research is conducted. Furthermore, the benefit of MABTs above and beyond CBT must be considered tentative at best; thus, CBT remains best practice for first-line treatment of SAD.

Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.

Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS.

Internet videoconferencing delivered cognitive behavioral therapy for social anxiety disoder: Protocol for a randomized controlled trial.

BACKGROUND: Social anxiety disorder (SAD) is characterized by a fear of scrutiny in social or performance situations. Due to a number of barriers, many individuals do not seek treatment for SAD, resulting in a chronic and debilitating course. Cognitive behaviour therapy (CBT), and more recently Imagery Rescripting (ImR), have been found to be efficacious in the treatment of SAD when delivered face-to-face. However, the efficacy of these treatment approaches when delivered remotely, have not yet been examined in controlled trials. METHODS: The authors propose a two-group randomized controlled trial comparing the efficacy of videoconferencing delivered CBT (vCBT) for SAD against a waitlist control group. The study will recruit 78 adults in total with a primary diagnosis of SAD of at least moderate severity. The manualised high-intensity vCBT intervention will be delivered weekly over an 8-week period. After treatment completion, the waitlist participants will receive a high-intensity videoconferencing delivered ImR (vImR) intervention also delivered weekly over an 8-week period. Treatment for both groups will be delivered in real time via an online videoconferencing platform. Outcome measures will be administered at baseline, mid-treatment, post-treatment, and 3-month follow-up. CONCLUSION: This trial will report findings on the efficacy of a remote synchronous high-intensity vCBT and vImR intervention for SAD and benchmark the two different treatment methodologies against standard face-to-face CBT. The results have the potential to inform best-practice remote psychological treatment for SAD. TRIAL REGISTRATION: The trial was registered on the Australian New Zealand Clinical Trials Registry; ACTRN12623000313639 (5 April 2023).