The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

Guiding task work in the context of an emotion-focused relationship.

In undertaking the complex process of being an emotion-focused therapist, one needs to strike a careful balance between providing a safe relational environment, while navigating with clients through their emotional world. In response to in-session verbal and non-verbal indicators, they invite clients to engage in chair work tasks designed to facilitate emotional exploration and deepening with a goal of emotional transformation. Therapists may be daunted by the prospect of introducing chair work tasks, and concerned about the impact on the relational bond. However, chair work tasks can deepen emotional exploration and shifts, and streamline the process of change. The case of Emma* will illustrate how therapists navigate the interplay between striking an empathic relationship and facilitating chair work tasks. The case will demonstrate how the therapist addresses hesitation or reluctance expressed by the client, while strengthening the bond and deepening emotional processing (*Pseudonym).

Case formulation in emotion-focused therapy.

Case formulation in emotion-focused therapy aids therapists to both conceptualize core emotion schemes and follow markers across therapy that signify tasks aimed at emotional transformation. The case formulation process will be illustrated in the successful case of Jina, a woman with a history of childhood emotional abuse who sought therapy for depression. The three stages of case formulation are co-constructed between client and therapist. In stage one, the therapist assesses her initial emotion processing style and listens as the emotion-based narrative unfolds. In stage two, the core emotion scheme and formulation narrative organize around feelings of shame of inferiority and attachment-related feelings of being rejected and unloved. Attendant secondary emotions of powerlessness, and unmet needs for validation emerge. Stage three evolves as the therapist follows process markers, prompting chair work for both unfinished business and self-criticism, ultimately helping Jina access adaptive sadness and newly experienced self-compassion.

Interventions for paternal perinatal depression: A systematic review.

BACKGROUND: The prevalence of paternal perinatal depression (PPD) is approximately 10%. Despite this epidemiology and what is known about the importance of paternal mental health to family functioning, there is limited research on evidence-based interventions for PPD. This systematic review aimed to investigate the literature for randomized-controlled trials (RCT) of interventions for PPD. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases searched included Medline, EMBASE, EBM Reviews, PubMed, PsycInfo, and CINAHL. Search terms included depression, depressive disorder, fathers, pregnancy, and peripartum period, etc. RESULTS: The search strategy identified 2949 items. A total of 10 interventions over the course of 25 years of research met inclusion criteria. Three of the included studies found a small but significant effect on paternal depression scores. However, none of the included studies exclusively targeted paternal mental health. Instead, they addressed paternal well-being indirectly by focusing on the mother, infant, or couple relationship. LIMITATIONS: Studies did not require fathers to meet criteria for depression at baseline. This may have resulted in a selection bias, whereby the included fathers may not have required any treatment. We were also unable to perform additional statistical analyses because of the limited research available as well as the inconsistent outcome measures. CONCLUSIONS: There remains limited research on interventions assessing paternal depressive symptomatology, and none have targeted diagnosed PPD. Because of the prevalence and impact of this disorder, it is imperative to identify and offer treatments and interventions specifically tailored towards this population.

A Scoping Review of Undocumented Immigrants and Palliative Care: Implications for the Canadian Context.

Approximately 30-40 million undocumented immigrants worldwide suffer restricted health care. A scoping review was conducted to determine what is known about this population's palliative end-of-life care experiences. The scoping review followed Arksey and O'Malley's methodological framework. Databases searched included CINAHL, Medline, ProQuest, Scopus, and PHRED. Search terms included uninsured care, palliative care, undocumented immigrants, and terminally ill. The search revealed limited peer-reviewed and grey literature on the topic. A total of six articles met inclusion criteria, of which four were case descriptions. Barriers to palliative care included lack of advanced care planning, lack of health insurance, poverty, fear of deportation, and limited English ability. Undocumented immigrants were more likely to have delayed access to and inadequate palliative end-of-life care. If palliative care is a human right, it is imperative that further research be conducted and policies put in place to better serve this vulnerable population at end-of-life.

"The Adopted Children of ART": expert clients and role tensions in ART provision in Uganda.

The implementation of the greater involvement of people living with HIV (GIPA) principle in Ugandan AIDS care is described by focusing on the engagement of expert clients in two rural health centers during a time of antiretroviral therapy (ART) scale-up. We contrast how the expert clients help overburdened nurses to manage the well-attended ART programs in the public and in the nongovernmental organization clinic. They are unpaid, but acquire preferential status in the ART program because of their knowledge of AIDS medicines (and its adverse effects) and because of the compassionate care that they provide. Despite the assistance provided, nurses in the public facility felt threatened in their professional status by these expert clients, who were seen to overstep the boundaries of their role. We pay particular attention to the double burden for HIV-positive nurses, who fear stigma, and (unlike the expert patients) keep their HIV status secret.