Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most ...promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
Parent-child interaction therapy (PCIT) is effective at reducing children's externalizing behavior. However, modifications are often made to PCIT, and it is not known whether these impact ...effectiveness.
To systematically review and meta-analyze the effects of PCIT on child externalizing behaviors, considering modifications, study design, and bias.
We searched PubMed, PsycINFO, Education Resources Information Center, Sociological Abstracts, and A+ Education.
We selected randomized controlled or quasi-experimental trials.
We analyzed child externalizing and internalizing behaviors, parent stress, parent-child interactions, PCIT format, and study design and/or characteristics.
We included 23 studies (1144 participants). PCIT was superior to control for reducing child externalizing (standardized mean difference SMD: -0.87, 95% confidence interval CI:-1.17 to -0.58). PCIT studies that required skill mastery had significantly greater reductions in externalizing behavior than those that did not (Mastery: SMD: -1.09, 95% CI: -1.44 to -0.73; Nonmastery: SMD: -0.51,95% CI: -0.85 to -0.17,
= .02). Compared with controls, PCIT significantly reduced parent-related stress (mean difference MD: -6.98, 95% CI: -11.69 to -2.27) and child-related stress (MD: -9.87, 95% CI: -13.64 to -6.09). Children in PCIT were observed to be more compliant to parent requests (SMD: 0.89, 95% CI: 0.50 to 1.28) compared with controls. PCIT effectiveness did not differ depending on session length, location (academic versus community settings), or child problems (disruptive behaviors only compared with disruptive behavior and other problems).
Results for parent-child observations were inconsistently reported, reducing the ability to pool important data.
PCIT has robust positive outcomes across multiple parent-reported and observed parent-child interaction measures, and modifications may not be required even when implemented in diverse populations.
1. Characterize the clinical and ethical challenges inherent in determining when to administer naloxone to palliative care patients.
2. Implement therapeutic guidelines at home institutions to ...provide guidance regarding the appropriate administration of naloxone for hospitalized palliative care patients.
Naloxone, an opioid antagonist and overdose reversal agent, is recommended by the CDC and other experts to reduce opioid-related risk. Many symptoms of opioid overdose—respiratory changes, agonal breathing, depressed mental status—are also observed in actively dying patients. Therefore, the role of naloxone is complicated in palliative care (PC) due to the physician's ethical duty “to do no harm”. Administering naloxone to actively dying patients can result in acute opioid withdrawal, potentially precipitating end-of-life pain and dyspnea. However, failing to provide naloxone to opiate-toxic patients could hasten death.
Ms. R was a 60-year-old woman with widely metastatic breast cancer admitted for hypoxia and transferred to the ICU for respiratory failure. She was started on IV morphine as needed for pain and dyspnea. Naloxone was ordered, per standard ICU protocol. Her condition worsened and she opted for comfort care with continued as-needed morphine. Shortly before passing away, she received IV naloxone without documented indication. The following day, another nurse brought her concern to the PC team that Ms. R may have died with uncontrolled symptoms due to naloxone.
Naloxone for PC patients requires a nuanced understanding of its risks and benefits. We propose that PC clinicians implement hospital-wide guidelines and training to ensure appropriate administration.
Clinical guidelines should: (1) exclude actively dying patients, (2) focus on objective vital sign data (respiratory rate, oxygen saturation, blood pressure) to identify patients at risk of death without reversal, (3) recommend supplemental oxygen and deep-breathing as initial interventions.
When naloxone is indicated, titration to the lowest dose required to reverse respiratory (not mental status) effects can minimize opioid withdrawal, pain, and dyspnea. The standard naloxone dose can be diluted and rebolused every 3 minutes.
Naloxone administration should be documented with vital signs and indication. We recommend an interdisciplinary huddle to debrief and adjust subsequent opioid doses.
IMPORTANCE: Generalized pustular psoriasis (GPP) is a chronic, orphan disease with limited epidemiological data. OBJECTIVE: To describe the clinical characteristics, treatments, longitudinal disease ...course, and disease-specific health care utilization among patients with GPP across the United States. DESIGN, SETTING, AND PARTICIPANTS: A retrospective longitudinal case series involving 95 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for GPP and were treated at 20 US academic dermatology practices between January 1, 2007, and December 31, 2018. MAIN OUTCOMES AND MEASURES: The primary outcome is to describe the patient characteristics, associated medical comorbidities, treatment patterns complications, and GPP–specific health care utilization. RESULTS: Sixty-seven of 95 patients (70.5%) were women (mean age, 50.3 years SD, 16.1 years). In the initial encounter, 35 patients (36.8%) were hospitalized and 64 (67.4%) were treated with systemic therapies. In total, more than 20 different systemic therapies were tried. During the follow-up period, 19 patients (35.8%) reported hospitalizations at a median rate of 0.5 hospitalizations per year (IQR, 0.4-1.6). Women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83). CONCLUSIONS AND RELEVANCE: Generalized pustular psoriasis is a rare, chronic disease without standard treatment and is associated with continued health care utilization over time.
Bystander intervention (BI) is a prevention approach commonly used for interpersonal violence, but is less studied for problematic alcohol use (PAU). Domestic graduate and international students' ...life experiences bring a unique context for the potential application of BI to PAU.
We conducted a mixed methods study that consisted of a needs assessment and focus groups at a southeastern university in the U.S. The aims of this study were to understand (1) differences in PAU BI opportunities for domestic graduate versus international students, (2) reasons for differences in PAU BI use, and (3) barriers/facilitators in use of PAU BI.
Overall, participants had few opportunities to use BI. Domestic graduate students had slightly more opportunities compared to international students. Most prominent reasons for lack of opportunities included not wanting to drive, the cost of drinking, and holding a graduate student identity (e.g. not interested in heavy drinking). Trusting others to be responsible for themselves was a common barrier noted for not using BI for PAU.
PAU BI programs should contextualize experiences of domestic graduate and international students to provide appropriate skill development that considers unique barriers and facilitators to intervention use.
IMPORTANCE: Palmoplantar pustulosis (PPP) is a is a chronic, orphan disease with limited epidemiological data. OBJECTIVE: To describe the clinical characteristics, treatments, longitudinal disease ...course, and health care utilization in adults with PPP across the US. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, longitudinal case series from 20 academic dermatology practices in the US included a consecutive sample of 197 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for PPP between January 1, 2007, and December 31, 2018. Data analysis was performed June 2020 to December 2020. MAIN OUTCOMES AND MEASURES: The primary outcome was to describe the patient characteristics, associated medical comorbidities, treatment patterns, complications, and PPP-specific health care utilization. RESULTS: Of 197 patients, 145 (73.6%) were female, and the mean (SD) age at presentation was 53.0 (12.6) years, with a mean (SD) follow-up time of 22.1 (28.0) months. On initial presentation, 95 (48.2%) patients reported skin pain, and 39 (19.8%) reported difficulty using hands and/or feet. Seventy patients (35.5%) were treated with systemic treatments, and use of more than 20 different systemic therapies was reported. In patients with at least 6 months of follow-up (n = 128), a median (IQR) of 3.7 (4-10) dermatology visits per year were reported; 24 (18.8%) patients had 5 or more visits during the study period. CONCLUSIONS AND RELEVANCE: In this case series, PPP was associated with persistent symptoms, continued health care utilization, and a lack of consensus regarding effective treatments, emphasizing the unmet medical need in this population. Additional research is necessary to understand treatment response in these patients.
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