The authors and the journal regret that the printed version of the above article contained a number of errors. The correct and final version follows. The authors would like to apologise for any ...inconvenience caused.
Training therapists in evidence-based treatments (EBTs) is a strategy for improving the quality of mental health care. State and county-wide initiatives have focused on increasing EBT implementation, ...however, many clients seen in community mental health agencies do not fit into the age or diagnostic requirements of available EBTs. Given the limited reach of some EBTs, questions remain about how EBT implementation efforts may lead to a broader change in general practice. This study aimed to understand the secondary impacts of receiving training in and delivering one EBT, Parent-Child Interaction Therapy (PCIT), on therapists’ general provision of mental health care to children on their caseload who were not receiving PCIT.
Twenty-three therapists providing PCIT in community settings participated in hour-long semi-structured interviews about their experiences providing PCIT and general children’s mental health treatment. Thematic analysis illuminated themes and subthemes related to how PCIT training impacted the therapists' general practice.
Three primary themes emerged regarding how training in and providing PCIT impacted therapists’ general practice: (1) Treatment toolbox, (2) Involving caregivers in treatment, and (3) Confidence working with children.
This study highlighted how receiving training in an EBT impacts therapists’ general provision of services, such that child clients who are not receiving a full course of PCIT could still be receiving elements of evidence-based practices associated with improved quality of care, such as enhanced caregiver engagement and use of progress measures. Therapists’ increased confidence and skill set garnered from EBT training could generalize to their larger practice, which has significant implications for improving client care.
•Parent-Child Interaction Therapy training impacts general child therapy practice.•Clients may receive secondary benefits from their therapists’ PCIT training.•Therapists describe gaining a treatment ...toolbox from PCIT training.•PCIT therapists report increasing caregiver involvement in child treatment.•PCIT therapists report increased confidence working with children.
Training therapists in evidence-based treatments (EBTs) is a strategy for improving the quality of mental health care. State and county-wide initiatives have focused on increasing EBT implementation, however, many clients seen in community mental health agencies do not fit into the age or diagnostic requirements of available EBTs. Given the limited reach of some EBTs, questions remain about how EBT implementation efforts may lead to a broader change in general practice. This study aimed to understand the secondary impacts of receiving training in and delivering one EBT, Parent-Child Interaction Therapy (PCIT), on therapists’ general provision of mental health care to children on their caseload who were not receiving PCIT.
Twenty-three therapists providing PCIT in community settings participated in hour-long semi-structured interviews about their experiences providing PCIT and general children’s mental health treatment. Thematic analysis illuminated themes and subthemes related to how PCIT training impacted the therapist’s general practice.
Three primary themes emerged regarding how training in and providing PCIT impacted therapists’ general practice: (1) Treatment toolbox, (2) Involving caregivers in treatment, and (3) Confidence working with children.
This study highlighted how receiving training in an EBT impacts therapists’ general provision of services, such that child clients who are not receiving a full course of PCIT could still be receiving elements of evidence-based practices associated with improved quality of care, such as enhanced caregiver engagement and use of progress measures. Therapists’ increased confidence and skill set garnered from EBT training could generalize to their larger practice, which has significant implications for improving client care.
Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing ...the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.
In recent years, the prevalence rates of children’s mental health disorders have increased with current estimates identifying that as many as 15–20% of children meet criteria for a mental health ...disorder. Unfortunately, the same robust parenting interventions which have long targeted some of the most common and the most treatable child concerns (e.g., externalizing, disruptive behavior, and aggression) have also shown consistently low rates of father engagement. This persistent issue of engagement comes in the wake of an increasingly large body of literature which highlights the unique positive contributions fathers make to children and families when they are engaged in parenting interventions. As the role fathers play in families shifts to become more inclusive of childcare responsibilities and less narrowly defined by financial contributions, it becomes increasingly important to understand how best to engage fathers in interventions that aim to enhance parenting efficacy and family outcomes such as coparenting. The current review examined intervention (e.g., format and setting) and implementation characteristics (e.g., training and agency-level changes) associated with father engagement. Particular attention is paid to studies which described father-specific engagement strategies (e.g., inviting fathers directly, father-only groups, and adapting intervention to incorporate father preferences). A total of 26 articles met inclusion criteria after screening and full-text review. Results indicate that father engagement (i.e., initiating treatment) remains low with 58% of studies either not reporting father engagement or having engagement rates below 50%. More than two-thirds of studies did not include specific father engagement strategies. Those that did focused on changes to treatment format (e.g., including recreational activities), physical treatment setting (e.g., in-home and school), and reducing the number of sessions required for father participation as the most common father-specific engagement strategies. Some studies reported efforts to target racially and ethnically diverse fathers, but review results indicated most participants identified as Non-Hispanic White. Interventions were largely standard behavioral parent training programs (e.g., PCIT and PMT) with few exceptions (e.g., COACHES and cultural adaptations), and very few agencies or programs are systematically making adjustments (e.g., extended clinic hours and changes to treatment format) to engage fathers. Recommendations for future directions of research are discussed including the impact of differential motivation on initial father engagement in treatment, the importance of continuing to support diverse groups of fathers, and the potential for telehealth to address barriers to father engagement.
Therapist anxious distress when delivering child mental health treatment has been understudied as a factor that contributes to the underuse of some evidence-based interventions (EBIs), such as ...time-out for children with disruptive behaviors. This study investigated therapist anxious avoidance of time-out using a three-part, vignette-based survey design. Therapists (n = 198) read a vignette of an in-session time-out and reported on their personal anxious distress and likelihood of discontinuing the implementation of time-out. Therapists also provided open-ended descriptions of challenges to delivering time-out. Therapists reported moderate anxious distress at time points 1 and 2 and lower anxious distress at time 3 when the time-out had resolved. Most therapists endorsed some avoidance of time-out. Binomial logistic regression analyses indicated that increased anxious distress corresponded with an increased probability of avoiding time-out delivery in the future. Qualitative reports expanded on challenges to implementing time-out. Findings suggest the importance of addressing therapist anxious distress when implementing children's mental health treatments.
Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline ...removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival.
Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant ...clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS.
•Mutational trajectories are defined by complex patterns of molecular heterogeneity in MDS, including lower-risk cases.•Therapeutic intervention dynamically reshapes mutational patterns often resulting in branched or independent evolution of MDS clones.
Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells ...during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo.
Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of ...gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or Dlg1 induces atf3 expression via aPKC but independent of Jun-N-terminal kinase (JNK) signaling. Strikingly, removal of Atf3 from Dlg1 deficient cells restores polarized cytoarchitecture, levels and distribution of endosomal trafficking machinery, and differentiation. Conversely, excess Atf3 alters microtubule network, vesicular trafficking and the partition of polarity proteins along the apicobasal axis. Genomic and genetic approaches implicate Atf3 as a regulator of cytoskeleton organization and function, and identify Lamin C as one of its bona fide target genes. By affecting structural features and cell morphology, Atf3 functions in a manner distinct from other transcription factors operating downstream of disrupted cell polarity.
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