Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Institutional experience report on the target contouring workflow in the radiotherapy department for stereotactic arrhythmia radioablation delivered on conventional linear accelerators.

PURPOSE: In stereotactic arrhythmia radioablation (STAR), the target is defined using multiple imaging studies and a multidisciplinary team consisting of electrophysiologist, cardiologist, cardiac radiologist, and radiation oncologist collaborate to identify the target and delineate it on the imaging studies of interest. This report describes the workflow employed in our radiotherapy department to transfer the target identified based on electrophysiology and cardiology imaging to the treatment planning image set. METHODS: The radiotherapy team was presented with an initial target in cardiac axes orientation, contoured on a wideband late gadolinium-enhanced (WB-LGE) cardiac magnetic resonance (CMR) study, which was subsequently transferred to the computed tomography (CT) scan used for treatment planning-i.e., the average intensity projection (AIP) image set derived from a 4D CT-via an axial CMR image set, using rigid image registration focused on the target area. The cardiac and the respiratory motion of the target were resolved using ciné-CMR and 4D CT imaging studies, respectively. RESULTS: The workflow was carried out for 6 patients and resulted in an internal target defined in standard anatomical orientation that encompassed the cardiac and the respiratory motion of the initial target. CONCLUSION: An image registration-based workflow was implemented to render the STAR target on the planning image set in a consistent manner, using commercial software traditionally available for radiation therapy.

'E koekoe te Tui, e ketekete te Kaka, e kuku te Kereru, The Tui chatters, the Kaka cackles, and the Kereru coos': Insights into explanatory factors, treatment experiences and recovery for Maori with eating disorders - A qualitative study.

BACKGROUND: Eating disorders are as common in Maori, the Indigenous people of Aotearoa-New Zealand, as they are in non-Maori; however, research has focused on the experiences of non-Maori. This paper will describe explanatory factors, treatment experiences and what helps with recovery for Maori. METHODS: Kaupapa Maori research methodology informed the methods and analysis. Fifteen semi-structured interviews comprised thirteen Maori participants with eating disorders (anorexia nervosa, bulimia nervosa and binge eating disorder) and two whanau (support network) members. A thematic analysis was undertaken by a first cycle of coding that used deductive structural coding to identify data describing participants' perceived causes of eating disorders, their experience of treatment and recovery. A second cycle of coding used inductive analysis with descriptive and pattern coding. RESULTS: Three overarching themes were antecedents (cumulative exposure), treatment (a system of complexities) and recovery (resource empowerment). Antecedents comprised cumulative exposure to body and sporting ideals and adversity as causal factors of eating disorders. In the treatment theme, a system of complexities critiqued rural settings for generalised mental health services, allocation of Maori cultural support, the economic burden of treatment, culturally incongruent treatment (methods, values) and a weight-focused discharge criterion. Recovery (resource empowerment) found appropriate health information, self-determination and connection to Maori culture and whanau aspirations helped with recovery. CONCLUSION: The diversity of birdcalls reminds us of the individuality of eating disorders. Health practitioners are reminded that just as the Tui, Kaka and Kereru possess their own unique birdcalls, so do Maori with eating disorders and their whanau have their own experiences, needs and required treatment responses.

Clinical factors and early life experiences associated with therapeutic alliance development in treatment for depression or binge eating.

OBJECTIVE: This study examines childhood and clinical factors theorized to impact therapeutic alliance development over the course of psychotherapy. METHOD: Raters assessed the therapeutic alliance of 212 client-therapist dyads, participating in two randomized controlled trials of schema therapy and cognitive behavioural therapy for binge eating or major depression, at three time points. Linear mixed models were used to characterize therapeutic alliance development over time and assess the influence of childhood trauma, perceived parental bonding, diagnosis and therapy type on scores. RESULTS: Participants differed in initial alliance ratings for all subscales but had similar growth trajectories in all but the patient hostility subscale. A diagnosis of bulimia nervosa or binge eating disorder predicted greater initial levels of client distress, client dependency and overall client contribution to a strong therapeutic alliance, compared with a diagnosis of depression. Therapy type, childhood trauma and perceived parental bonds did not predict alliance scores. CONCLUSION: Findings highlight the potential influence of clinical and personal characteristics on alliance strength and development, with implications for maximizing treatment outcomes through anticipating and responding to these challenges.

Mapping anorexia nervosa genes to clinical phenotypes.

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

A Tale of Childhood Loss, Conditional Acceptance and a Fear of Abandonment: A Qualitative Study Taking a Narrative Approach to Eating Disorders.

Eating disorders (EDs) are serious mental health illnesses, yet there is a need to better understand the illness experience to improve treatment outcomes. Qualitative research, and narrative approaches in particular, can elicit life stories that allow for the whole illness journey to be explored. This study aimed to explore the experiences of women with a history of an ED, identifying the life events they perceived were relevant to the onset of their ED through to recovery. Interviews were conducted with 18 women with lived experience of an ED. Through structural narrative analysis, an overarching storyline of childhood loss contributing to a belief of conditional acceptance, fear of abandonment and struggle to seek emotional support due to the fear of being a burden was identified. Negative experiences with the health sector were common. These findings have implications for the way medical professionals respond to help seeking and deliver treatment.

Exercise Cardiovascular Magnetic Resonance: A Review.

While pharmacologic stress cardiovascular magnetic resonance imaging (MRI) is a robust noninvasive tool in the diagnosis and prognostication of epicardial coronary artery disease, clinical guidelines recommend exercise-based testing in those patients who can exercise. This review describes the development of exercise cardiovascular MRI protocols, summarizes the insights across various patient populations, and highlights future research initiatives. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

A randomised controlled trial of psychotherapy and cognitive remediation to target cognition in mood disorders.

OBJECTIVE: To examine the impact of a treatment package combining Interpersonal and Social Rhythm Therapy (IPSRT) and cognitive remediation (CR), vs IPSRT alone, on cognition, functioning, and mood disturbance outcomes in mood disorders. METHODS: A pragmatic randomised controlled trial in adults with bipolar disorder (BD) or major depressive disorder (MDD), recently discharged from mental health services in Christchurch, New Zealand, with subjective cognitive difficulties. Individuals were randomised to a 12-month course of IPSRT with CR (IPSRT-CR), or without CR (IPSRT). In IPSRT-CR, CR was incorporated into therapy sessions from approximately session 5 and continued for 12 sessions. The primary outcome was change in Global Cognition (baseline to 12 months). RESULTS: Sixty-eight individuals (BD n = 26, MDD n = 42; full/partial remission n = 39) were randomised to receive IPSRT-CR or IPSRT (both n = 34). Across treatment arms, individuals received an average of 23 IPSRT sessions. Change in Global Cognition did not differ between arms from baseline to treatment-end (12 months). Psychosocial functioning and longitudinal depression symptoms improved significantly more in the IPSRT compared with IPSRT-CR arm over 12 months, and all measures of functioning and mood symptoms showed moderate effect size differences favouring IPSRT (0.41-0.60). At 18 months, small to moderate, non-significant benefits (0.26-0.47) of IPSRT vs IPSRT-CR were found on functioning and mood outcomes. CONCLUSIONS: Combining two psychological therapies to target symptomatic and cognitive/functional recovery may reduce the effect of IPSRT, which has implications for treatment planning in clinical practice and for CR trials in mood disorders.

Specialist supportive clinical management for anorexia nervosa: Analysis of therapy content and relation to outcome.

OBJECTIVE: Psychotherapy for anorexia nervosa (AN) is complex and multifaceted, with little known about likely effective components of treatments. The current study explored the spoken content of specialist supportive clinical management (SSCM) for AN, a treatment with evidence of effectiveness in several randomized clinical trials. METHOD: One hundred seventy-eight therapy sessions constituting all ten therapist-patient dyads of those who completed SSCM treatment in the original clinical trial of SSCM, were transcribed verbatim. Themes were developed and content analyzed using qualitative content analysis of complete therapy sessions by four analysts, with 10% of sessions cocoded for interrater agreement. RESULTS: Over three quarters of session content was within the clinical management theme, the largest subtheme relating to normalizing eating, followed by weight, mechanics of SSCM, and encouragement of self-care. Approximately 20% of total content was in the supportive psychotherapy theme, half about relationships. The relative proportion of clinical management content remained high, decreasing during the last five sessions. Those achieving good outcome did not have a lower ratio of clinical management to supportive psychotherapy content. DISCUSSION: The current study revealed strong clinical management focus on core symptoms of AN-normalization of eating and weight gain-throughout SSCM for AN. PUBLIC SIGNIFICANCE: Six clinical trials have found SSCM to be effective in treating AN. Content of SSCM sessions in the original trial was classified using qualitative content analysis. Study findings revealed strong clinical management focus on core AN symptoms-normalization of eating and weight gain-throughout SSCM, with the ratio of clinical management to supportive psychotherapy greater for those with a good outcome.

Randomised controlled trial of Interpersonal and Social Rhythm Therapy and group-based Cognitive Remediation versus Interpersonal and Social Rhythm Therapy alone for mood disorders: study protocol.

BACKGROUND: Individuals with mood disorders frequently experience cognitive impairment, which impacts on the long-term trajectory of the disorders, including being associated with persisting difficulties in occupational and psychosocial functioning, residual mood symptoms, and relapse. Current first-line treatments for mood disorders do little to improve cognitive function. Targeting cognition in clinical research is thus considered a priority. This protocol outlines a prospectively-registered randomised controlled trial (RCT) which examines the impact of adding group-based Cognitive Remediation (CR) to Interpersonal and Social Rhythm Therapy (IPSRT-CR) for individuals with mood disorders. METHODS: This is a pragmatic, two-arm, single-blinded RCT comparing IPSRT-CR with IPSRT alone for adults (n = 100) with mood disorders (Major Depressive Disorder or Bipolar Disorder) with subjective cognitive difficulties, on discharge from Specialist Mental Health Services in Christchurch, New Zealand. Both treatment arms will receive a 12-month course of individual IPSRT (full dose = 24 sessions). At 6 months, randomisation to receive, or not, an 8-week group-based CR programme (Action-based Cognitive Remediation - New Zealand) will occur. The primary outcome will be change in Global Cognition between 6 and 12 months (treatment-end) in IPSRT-CR versus IPSRT alone. Secondary outcomes will be change in cognitive, functional, and mood outcomes at 6, 12, 18, and 24 months from baseline and exploratory outcomes include change in quality of life, medication adherence, rumination, and inflammatory markers between treatment arms. Outcome analyses will use an intention-to-treat approach. Sub-group analyses will assess the impact of baseline features on CR treatment response. Participants' experiences of their mood disorder, including treatment, will be examined using qualitative analysis. DISCUSSION: This will be the first RCT to combine group-based CR with an evidence-based psychotherapy for adults with mood disorders. The trial may provide valuable information regarding how we can help promote long-term recovery from mood disorders. Many issues have been considered in developing this protocol, including: recruitment of the spectrum of mood disorders, screening for cognitive impairment, dose and timing of the CR intervention, choice of comparator treatment, and choice of outcome measures. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12619001080112 . Registered on 6 August 2019.

Long-term efficacy of metacognitive therapy and cognitive behaviour therapy for depression.

OBJECTIVE: To examine the two-year outcomes for depression, anxiety, cognitive and global social functioning after cognitive behavioural therapy (CBT) and metacognitive therapy (MCT) for depression. METHOD: Participants were 31 adults with a diagnosis of major depressive disorder in a randomised pilot study comparing MCT and CBT. Therapy modality differences in change in depression and anxiety symptoms, dysfunctional attitudes, metacognitions, rumination, worry and global social functioning were examined at the two-year follow-up for those who completed therapy. RESULTS: Significant improvements, with large effect sizes, were evident for all outcome variables. There were no significant differences in outcome between CBT and MCT. The greatest change over time occurred for depression and anxiety. Large changes were evident for metacognitions, rumination, dysfunctional attitudes, worry and global social functioning. Sixty-seven percent had not experienced a major depression and had been well during all of the past year, prior to the follow-up assessment. CONCLUSION: The finding at end treatment, of no modality specific differences, was also evident at two-year follow-up. Although CBT and MCT targeted depression, improvements were much wider, and although CBT and MCT take different approaches, both therapies produced positive change over time across all cognitive variables. CBT and MCT provide treatment options, that not only improve the longer-term outcome of depression, but also result in improvements in anxiety, global social functioning and cognitive status.

Role of Cardiac MRI Imaging of Focal and Diffuse Inflammation and Fibrosis in Cardiomyopathy Patients Who Have Pacemakers/ICD Devices.

PURPOSE OF REVIEW: This focused report aims to discuss and summarize the use of conventional and emerging methods using cardiovascular magnetic resonance (CMR) imaging in cardiomyopathy patients with implanted cardiac devices to identify diffuse and focal inflammation and fibrosis. RECENT FINDINGS: Many cardiomyopathy patients with diffuse and focal myocardial fibrosis have a unique need for cardiac imaging that is complicated by cardiovascular implantable electronic devices (CIEDs). CMR imaging can accurately image myocardial fibrosis and inflammation using T1 mapping and late gadolinium enhancement (LGE) imaging. CMR imaging in CIED patients, however, has been limited due to severe imaging artifacts associated with the devices. The emergence of wideband imaging variants of LGE and T1 mapping techniques can successfully reduce or eliminate CIED artifacts for the evaluation of myocardial substrate in cardiomyopathy patients. Wideband imaging variants of LGE and T1 mapping techniques provide new tools for imaging focal and diffuse fibrosis and imaging in cardiomyopathy patients with implanted cardiac devices. These emerging techniques have the potential for great impact in clinical care of such patients as well as clinical research where imaging endpoints are desired.

The effect of temperament and character on body dissatisfaction in women with bulimia nervosa: The role of low self-esteem and depression.

OBJECTIVE: Although personality traits have been found to be associated with body dissatisfaction for women in the general population, little research has explored these associations for people with eating disorders. Furthermore, it is unknown whether these associations are direct or are mediated by other factors. In this cross-sectional study, secondary analyses of data from two clinical trials were conducted to determine which personality dimensions contributed to body dissatisfaction in women with bulimia nervosa, and whether low self-esteem and depression mediate these associations independently or in serial. METHOD: Participants were 193 women with bulimia nervosa. Participants completed self-report measures of temperament and character, body dissatisfaction, low self-esteem, and depression before receiving treatment for their eating disorder. RESULTS: The temperament dimension, harm avoidance, contributed significantly to body dissatisfaction. Serial mediation analyses showed this association was fully mediated, revealing two significant indirect effects. The first was through low self-esteem and the second through depression and low self-esteem in serial. CONCLUSIONS: Findings suggest body dissatisfaction in women with bulimia nervosa may be indirectly targeted through addressing harm avoidance, depression and low self-esteem.

Personality traits and night eating syndrome in women with bulimia nervosa and binge eating disorder.

PURPOSE: Previous research suggests that eating disorders may be associated with certain personality profiles; however, there is limited research investigating associations with night eating syndrome (NES). This research suggests harm avoidance personality trait is higher in NES individuals than in the general population, however, evidence of associations with other personality traits is inconsistent. To understand which personality traits are associated with NES symptoms, the current study aimed to improve understanding of the relationship between NES symptoms and a range of personality traits, addressing limitations in the earlier literature in this area by controlling for common confounders. METHODS: Baseline data were analysed from an outpatient psychotherapy trial for 111 women with bulimia nervosa or binge eating disorder. Pre-treatment measures of personality traits (measured with the Temperament and character inventory-revised) and NES symptoms (measured with the Night eating questionnaire) were used. Regression analyses tested associations between these variables, adjusting for potential confounders, including age and ethnicity. RESULTS: Low cooperativeness scores were associated with greater NES symptoms in the multivariable model (mean difference: - 0.10, 95% confidence intervals: - 0.20 to - 0.01, p = 0.033). There was weak evidence of associations between both high harm avoidance and low self-directedness personality traits and greater NES symptoms. CONCLUSIONS: This study adds to the limited research measuring associations between a range of personality traits and NES, addressing limitations of previous research. Weak evidence for an association between high harm avoidance and low self-directedness and increased NES symptoms was found. A novel association was found between low cooperativeness and greater NES symptoms. Further research is needed to validate its presence in those with and without comorbid eating disorders and to examine the relative change in NES, eating disorder symptoms and personality scores in treatments focusing on cooperativeness. LEVEL OF EVIDENCE: Level IV (cross-sectional data from a randomised controlled trial, CTB/04/08/139).

Recommendations to encourage participation of individuals from diverse backgrounds in psychiatric genetic studies.

We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for various psychiatric disorders across all demographic groups. We present approaches developed as part of the Eating Disorders Genetics Initiative (EDGI), a study that required tailored approaches to recruit diverse populations across many countries. Considerations include research priorities and design, recruitment and study branding, transparency, and community investment and ownership. Ensuring representation in participants is costly and funders need to provide adequate support to achieve diversity in recruitment in prime awards, not just as supplemental afterthoughts. The need for diverse samples in genetic studies is critical to minimize the risk of perpetuating health disparities in psychiatry and other health research. Although the EDGI strategies were designed specifically to attract and enroll individuals with eating disorders, our approach is broadly applicable across psychiatry and other fields.

Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART).

BACKGROUND: Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. METHODS: Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. DISCUSSION: The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BACKGROUND: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder. METHODS: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). DISCUSSION: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .

Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis.

Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.

Patients' Perceptions of Functional Improvement in Psychotherapy for Mood Disorders.

OBJECTIVE: This study aimed to examine participants' experiences of interpersonal and social rhythm therapy, with or without cognitive remediation, and the impact of this intervention on their functioning. METHODS: This qualitative study drew data from follow-up interviews of 20 participants who completed the 12-month intervention as part of a randomized controlled trial. The qualitative data were collected through semistructured interviews and were analyzed with thematic analysis. RESULTS: The 20 participants (11 men, 9 women, ages 22-55, median age=32) reported that interpersonal and social rhythm therapy (content and process) as an adjunct to medication, alone or in combination with cognitive remediation, was effective in improving their functioning. They described these improvements as facilitated by a new sense of control and confidence, ability to focus, new communication and problem-solving skills, and better daily routines. CONCLUSIONS: Participants with recurrent mood disorders described improved functioning related to therapies that formulate their mood disorder in terms of a model, such as interpersonal and social rhythm therapy with or without cognitive remediation, that provides an understandable and evidence-based rationale, facilitates a sense of control and confidence by supporting the person in undertaking practical routines that can be integrated into daily life, focuses on communication and problem-solving skills, and engenders a sense of hope by working with the person to develop self-management strategies relevant to their specific symptom experiences and the life they choose to live.