Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

Long Non-Coding RNAs as "MYC Facilitators".

In this article, we discuss a class of MYC-interacting lncRNAs (long non-coding RNAs) that share the following criteria: They are direct transcriptional targets of MYC. Their expression is coordinated with the expression of MYC. They are required for sustained MYC-driven cell proliferation, and they are not essential for cell survival. We refer to these lncRNAs as "MYC facilitators" and discuss two representative members of this class of lncRNAs, SNHG17 (small nuclear RNA host gene) and LNROP (long non-coding regulator of POU2F2). We also present a general hypothesis on the role of lncRNAs in MYC-mediated transcriptional regulation.

Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα).

Recent cryo-electron microscopic (cryo-EM) investigations have succeeded in the analysis of various structural conformations and functional states of PI3Kα, a dimer consisting of the catalytic subunit p110α and the regulatory subunit p85α of class IA of phosphoinositide 3-kinase. High resolution structures have been obtained of the unliganded and of BYL-719-bound PI3Kα. The latter provides information on excessively flexible domains of p85α that are then further analyzed with nanobodies and CXMS (chemical cross-linking, digestion and mass spectrometry). Analysis of p110α helical and kinase domain mutations reveals mutant-specific features that can be linked to the gain of function in enzymatic and signaling activities.

The MYC-regulated lncRNA LNROP (ENSG00000254887) enables MYC-driven cell proliferation by controlling the expression of OCT2.

MYC controls most of the non-coding genome. Several long noncoding transcripts were originally identified in the human B cell line P496-3 and then shown to be required for MYC-driven proliferation of Burkitt lymphoma-derived RAMOS cells. In this study, we used RAMOS cells exclusively as a representative of the human B cell lineage. One of the MYC-controlled lncRNAs required for RAMOS cell proliferation is ENSG00000254887 which we will term LNROP (long non-coding regulator of POU2F2). In the genome, LNROP is located in close proximity of POU2F2, the gene encoding OCT2. OCT2 is a transcription factor with important roles in sustaining the proliferation of human B cells. Here we show that LNROP is a nuclear RNA and a direct target of MYC. Downregulation of LNROP attenuates the expression of OCT2. This effect of LNROP on the expression of OCT2 is unidirectional as downregulation of OCT2 does not alter the expression of LNROP. Our data suggest that LNROP is a cis-acting regulator of OCT2. To illustrate the downstream reach of LNROP, we chose a prominent target of OCT2, the tyrosine phosphatase SHP-1. Downregulation of OCT2 elevates the expression of SHP-1. Our data suggest the following path of interactions: LNROP enables the proliferation of B cells by positively and unidirectionally regulating the growth-stimulatory transcription factor OCT2. In actively proliferating B cells, OCT2 attenuates the expression and anti-proliferative activity of SHP-1.

Effectiveness of Single Chest Tube vs Double Chest Tube Application Postdecortication: Prospective Randomized Controlled Study.

BACKGROUND: Draining the chest cavity with 2 tubes is a common practice among thoracic surgeons. This research was conducted in Addis Ababa from March 2021 to May 2022. A total of 62 patients were included. STUDY DESIGN: This study was conducted to investigate the superiority of either single or double tube insertion after decortication. Patients were randomized in a ratio of 1:1. In group A, 2 tubes were inserted; in group B, single 32F tubes were inserted. Statistical analyses were performed using Statistical Package for Social Sciences version 27.0, Student's t test and Pearson chi-square test. RESULTS: The age range of patients was 18 to 70 years, with a mean of 44 ± 14.4434 years; the male to female ratio was 2.9:1. The dominant underlying pathologies were tuberculosis and trauma (45.2% vs 35.5%); the right side was more involved (62.3%). Drain output was 1,465 ± 1,887.9751 mL in group A vs 1,018 ± 802.5662 mL in group B (p value = 0.00001); the duration of drains was 7.5498 ± 11.3137 days in group A vs 3.8730 ± 1.4142 days in group B (p value = 0.000042). The degree of pain was 2.6458 ± 4.2426 vs 2.000 ± 2.1213 in group A and group B, respectively (p value = 0.326757). The length of hospital stay was 21.5818 ± 11.9791 days in group A vs 13.6091 ± 6.2048 days in group B (p value = 0.00001). Group A had air leak of 90.3% vs 74.2% in group B; subcutaneous emphysema was 9.7% in group A and 12.9% in group B. There was no fluid recollection, and no patients required tube reinsertion. CONCLUSIONS: The placement of a single tube after decortication is effective in reducing drain output, time of drain, and hospital stay. There was no association with pain, and there was no effect on other endpoints.

How do the working lives of general practitioners in rural areas compare with elsewhere in Scotland? Cross-sectional analysis of the Scottish School of Primary Care Survey.

INTRODUCTION: The shortage of GPs in Scotland is concerning, particularly in rural areas. There are many reasons why GPs are leaving general practice; however, satisfaction with working life is an important predictor of GP retention. The aim of this study was to compare the working lives and intentions to reduce work participation of rural GPs and GPs working elsewhere in Scotland. METHODS: Quantitative analysis of responses from a nationally representative survey of GPs in Scotland. GPs were classified as 'non-rural' or 'rural' and these groups were compared using univariate and multivariate statistical analysis on four domains of working lives (job satisfaction, job stressors and positive and negative job attributes) and four intentions to reduce work participation (reducing working hours, working abroad, leaving direct patient care and leaving medical work entirely). RESULTS: There were significant differences in characteristics between rural and non-rural GPs. After controlling for these differences, GP age and gender, rural GPs reported higher job satisfaction, lower job stressors, higher positive job attributes, and lower negative job attributes than GPs elsewhere. A significant interaction between gender and rurality was found for job satisfaction, indicating that it was rural female GPs who were more satisfied. Rural GPs were, however, more likely to intend to work abroad and leave medical work entirely within 5 years than other GPs. DISCUSSION: These findings corroborate research from around the world and have serious implications for the future care of patients in rural areas. Further research is urgently required to understand the drivers of these findings.

A Statewide Randomized Controlled Trial to Compare Three Models for Implementing Parent Child Interaction Therapy.

OBJECTIVE: This study (NIMH RO1 MH095750; ClinicalTrials.gov Identifier: NCT02543359) evaluated the effectiveness of three training models to implement a well-established evidence-based treatment, Parent-Child Interaction Therapy (PCIT). METHOD: Fifty licensed outpatient clinics, including 100 clinicians, 50 supervisors, and 50 administrators were randomized to one of three training conditions: 1) Learning Collaborative (LC), 2) Cascading Model (CM) or 3) Distance Education (DE). Data to assess training and implementation outcomes were collected at 4 time points coinciding with the training period: baseline, 6- (mid), 12- (post), and 24-months (1-year follow-up). RESULTS: Multi-level hierarchical linear growth modeling was used to examine changes over time in training outcomes. Results indicate that clinicians in CM were more likely to complete training, reported high levels of training satisfaction and better learning experiences compared to the other training conditions. However, supervisors in the LC condition reported greater learning experiences, higher levels of knowledge, understanding of treatment, and satisfaction compared to supervisors in other conditions. Although clinicians and supervisors in the DE condition did not outperform their counterparts on any outcomes, their performance was comparable to both LC and CM in terms of PCIT use, supervisor perceived acceptability, feasibility, system support, and clinician satisfaction. CONCLUSIONS: Through the use of a randomized controlled design and community implementation, this study contributes to the current understanding of the impact of training design on implementation of PCIT. Results also indicate that although in-person training methods may produce more positive clinician and supervisor outcomes, training is not a one-size-fits-all model, with DE producing comparable results on some variables.

Sexual Offense Disclosure Assessment in Youth Referred to Community Treatment: A Latent Class Analysis.

This study seeks to extend research evaluating tools to assess the disclosure of sexually abusive behavior. The subjects were 239 male youth (ages 10-20 years) who were court-ordered to participate in a community-based collaborative intervention for sexual offending that includes outpatient and probationary services. All youth participated in an interview to capture referral incident details about admission, responsibility, empathy, and remorse at intake, during intervention, and at discharge. Intake, treatment, discharge, and recidivism measures were also collected from multiple sources. Latent class analysis identified three classes based on the intake interview: Empathetic Admitters (22%), Unempathetic Admitters (38%), and Unempathetic Deniers (40%). Significant class differences were found on intake (e.g., use of physical force, caregiver denial of youth responsibility), treatment (e.g., any sanctions/violations), and discharge measures (e.g., successful treatment, probation officer ratings), but not in recidivism rates. The findings extend efforts to identify and target different disclosure patterns whose clinical monitoring may support a comprehensive intervention.

Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα.

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer consisting of a catalytic subunit, p110α, and a regulatory subunit, p85α, and is referred to as PI3Kα. The catalytic subunit p110α is frequently mutated in cancer. The mutations induce a gain of function and constitute a driving force in cancer development. About 80% of these mutations lead to single-amino-acid substitutions in one of three sites of p110α: two in the helical domain of the protein (E542K and E545K) and one at the C-terminus of the kinase domain (H1047R). Here, we report the cryo-electron microscopy structures of these mutants in complex with the p110α-specific inhibitor BYL-719. The H1047R mutant rotates its sidechain to a new position and weakens the kα11 activation loop interaction, thereby reducing the inhibitory effect of p85α on p110α. E542K and E545K completely abolish the tight interaction between the helical domain of p110α and the N-terminal SH2 domain of p85α and lead to the disruption of all p85α binding and a dramatic increase in flexibility of the adaptor-binding domain (ABD) in p110α. Yet, the dimerization of PI3Kα is preserved through the ABD-p85α interaction. The local and global structural features induced by these mutations provide molecular insights into the activation of PI3Kα, deepen our understanding of the oncogenic mechanism of this important signaling molecule, and may facilitate the development of mutant-specific inhibitors.

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα.

Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.

Unique cessation tools in the box: Quitline utilization and effectiveness trends among a large sample of tobacco users reporting mental health disorders.

It is estimated that the prevalence of smoking among adults with MHDs ranges between 40-60%, as compared to about 17% among those without an MHD. In addition, smokers with MHDs smoke more cigarettes, are more nicotine dependent, and experience more difficulty quitting, compared to other smokers. The uniquely high smoking prevalence among the MHD population is a serious public health concern; unfortunately, a majority of individuals experiencing difficulty receive no treatment. The US Public Health Service guidelines, as well as the National Cancer Institute, strongly recommend quitlines as an evidence-based treatment strategy to reduce barriers to cessation treatment, especially among smokers with MHDs; however, the literature is sparse on quitline engagement trends and associated outcomes for quitline participants with MHDs. This study sought to contribute to this gap with the largest sample to-date of MHD-endorsing tobacco quitline (Oklahoma Tobacco Helpline, OTH) participants. From 2015 to 2020, ~65,000 registrants (45-50% of total registered participants) with the OTH identified as having one or more MHDs in addition to their tobacco use. This study tested for the presence of significant differences between groups with and without MHDs (as well as within the MHD-identified group) on program enrollment selections, the intensity of engagement with chosen services, NRT utilization, and quit rates. It also tested for the existence of differences and moderating effects of demographic variables associated with the comparison groups. Statistically significant differences were found between these two groups with regard to: sex, age, racial identity, education level, annual income and insurance status. Significant differences were also found with tobacco use patterns reported by individuals (e.g., timing and daily use amounts). Differences in quitline program selection were demonstrated, such that the MHD-endorsing sample were more likely to participate and agree to the most robust service available. Significantly higher rates of service intensity (number of services engaged) were demonstrated, and MHD individuals were also significantly more likely to receive NRT as a part of their treatment. This study suggests a simplistic "more is better" quitline services approach may suffer in effectiveness because it neglects barriers common to this population. Important information is provided on these unique variables associated with MHD-endorsing individuals trying to quit their tobacco use. These results can help tobacco quitlines conceptualize the unique difficulties experienced by individuals with MHDs and then tailor their approach to respond supportively and constructively to this high need group.

How do the working lives of general practitioners in rural areas compare with elsewhere in Scotland? Cross-sectional analysis of the Scottish School of Primary Care National GP Survey.

INTRODUCTION: Like many countries around the world, Scotland faces a shortage of general practitioners (GPs) due to both recruitment and retention issues. Such workforce shortages are of particular concern in rural areas. There are many reasons why GPs are leaving general practice; however, satisfaction with working life is an important predictor of GP retention. It is important, therefore, to understand working life satisfaction of rural GPs. The purpose of this study was to compare the working lives and intentions to reduce work participation of rural GPs and GPs working elsewhere in Scotland. METHODS: This study was a quantitative analysis of survey data from the Scottish School of Primary Care national working lives survey. GPs were classified as working in 'non-rural' or 'rural' practices based on the Scottish Government's rural binary classification system, and were compared using univariate and multivariate statistical analysis on four domains of working lives: job satisfaction, job stressors, positive and negative job attributes, and four intentions to reduce work participation: reducing working hours, working abroad, leaving direct patient care and leaving medical work entirely. RESULTS: A total of 2465 GPs returned the survey, giving a response rate of 56%. Three-hundred and forty seven GPs who returned the survey worked in practices in rural areas (14.1%). Rural GPs were more likely to do out-of-hours work (p<0.001), to have worked in their practice for fewer years (p=0.014), to work in single-GP partnerships (p<0.001), and to work in practices with smaller list sizes (p<0.001), than GPs in non-rural settings. Compared with GPs elsewhere, rural GPs reported higher mean job satisfaction (5.23 v 5.39, respectively; p<0.005), lower mean job stressors (3.58 v 3.29; p<0.001) and lower mean negative job attributes (4.08 vs 3.78; p<0.001). These differences remained highly significant after controlling for potential confounders (age, gender and the differences in work practices shown above). In regression analysis, a significant interaction was found between gender and rurality for job satisfaction (p=0.008), which indicated that rural female GPs' higher job satisfaction mainly accounted for rural GPs' increased job satisfaction. No significant interaction was found between gender and rurality for the other domains of working lives. Compared with GPs elsewhere, however, rural GPs were more likely to intend to work abroad (mean 1.39 v 1.55; p=0.013) and leave medical work entirely within 5 years (mean 2.15 v 2.36; p=0.039). These intentions remained significant after controlling for potential confounders. No significant interaction was found between gender and rurality for variables for intentions to reduce work participation. CONCLUSION: Rural GPs in Scotland are more satisfied with their working lives than GPs working elsewhere in Scotland, which is mainly due to higher job satisfaction in female GPs in rural areas. Despite this, rural GPs as a whole have a higher intention to leave their job in the next 5 years than their non-rural counterparts. Although some of these differences are small, they may signal serious implications for the future care of patients in rural areas and require further research to understand the drivers of this.

A Randomized Pilot of a Tailored Smoking Cessation Quitline Intervention for Individuals Who Smoke and Vape.

INTRODUCTION: Although e-cigarettes are not a federally approved tobacco cessation aid in the United States, many smokers use them to quit or cut down on smoking. Tailored behavioral support could improve rates of complete smoking cessation for those individuals. AIMS AND METHODS: A novel behavioral treatment to help dual cigarette and e-cigarette users quit smoking was tested in a randomized pilot with a state tobacco quitline. Ninety-six dual users of cigarettes and e-cigarettes were recruited from incoming state quitline callers and randomized to receive enhanced e-cigarette coaching (EEC) or quitline treatment as usual (TAU) to examine EEC feasibility and acceptability. Outcomes at 3 months were treatment satisfaction, engagement, beliefs, and smoking cessation. This pilot was not powered to detect differences in quit rates. RESULTS: Sixty-nine percent responded to the 3-month survey. EEC treatment satisfaction was noninferior to TAU: 93.8% (30/32) of EEC and 73.5% (25/34) of TAU reported being "very satisfied" or "satisfied" with treatment, respectively. EEC participants completed more coaching calls than TAU (M = 3.4 vs. M = 2.7, p = .03), and the majority in both groups elected to receive nicotine replacement therapy (EEC: 100%, TAU: 94%, p = .24). With missing data imputed as smoking, intent-to-treat 7-day point prevalence smoking abstinence rates were 41.3% (19/46) for EEC and 28.0% (14/50) for TAU (p = .20). CONCLUSIONS: The EEC quitline intervention for dual cigarette and e-cigarette users demonstrated high levels of treatment satisfaction and engagement. This pilot was not powered to detect significant differences in smoking cessation; however, cessation rates were promising and warrant evaluation in a fully powered trial. IMPLICATIONS: If this scalable behavioral treatment to help dual cigarette and e-cigarette users quit smoking proves to be effective in a larger trial, quitlines could implement this harm reduction approach to improve outcomes for callers who already use e-cigarettes and are planning to use them while quitting smoking.

An unusual manifestation of hydatid disease: A case in a 20-year old male patient.

Echinococcosis is a re-emerging public health issue in developing countries as most communities are homes to dogs and other domesticated animals while cattle raising is a major habit of most sub-Saharan countries. The usual presentations include liver and lung cysts. While few documentations and publications have been made on extra-pulmonary intrathoracic hydatid cysts in other parts of the world, there has been no published document on extra-pulmonary intrathoracic hydatid cysts consisting of eighty or more cystic masses in a single patient in Ethiopia. We present a case of right sided extra-pulmonary intrathoracic hydatid cysts in a 20-year old Ethiopian male patient with compressive respiratory symptoms and significant social history of cohabiting with dogs throughout childhood. The patient was treated by surgery via a posterolateral thoracotomy and had a smooth Post-operative course and discharged home on postoperative day 15 on albendazole and analgesics. Intraoperative findings included approximately 1500 ml of cystic fluid, eighty cystic masses and collapsed lung.

Rare presentation of sarcoidosis with optic neuropathy and third nerve palsy.

Sarcoidosis is a systemic, idiopathic and granulomatous disease, which most commonly affects the skin, lungs and lymph nodes but can affect virtually any organ. Neurosarcoidosis can be the presenting or the only clinical manifestation accounting for 5%-15% of sarcoid diagnoses. In contrast to uveitis which is the most common ophthalmic manifestation, neuro-ophthalmic signs are uncommon in sarcoidosis. Optic neuropathy is the most common neuro-ophthalmic sign (70% in one series). Sarcoid-related optic neuropathy commonly presents with a picture similar to optic neuritis. Less commonly, optic nerve involvement occurs secondary to compressive lesions, or from direct granulomatous infiltration. Neuroimaging is crucial to identify the location of the lesion. We describe a case of sarcoid-related compressive optic neuropathy and third nerve palsy and highlight the challenging nature of neurosarcoidosis in a patient without a prior diagnosis of the disease.

Cryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation.

Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3Kα (p110α-p85α): the unliganded heterodimer PI3Kα, PI3Kα bound to the p110α-specific inhibitor BYL-719, and PI3Kα exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3Kα are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3Kα, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3Kα activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3Kα, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3Kα, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3Kα is composed of a stable core resolved at 3.8 Å. It contains all p110α domains except the adaptor-binding domain (ABD). The p85α domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3Kα by fully releasing the niSH2 domain from binding to p110α. The structures presented here show the basal form of the full-length PI3Kα dimer and document conformational changes related to the activated and inhibited states.

Treatment development, implementation, and participant baseline characteristics: A randomized pilot study of a tailored quitline intervention for individuals who smoke and vape.

BACKGROUND: Approximately 57,000 dual users of cigarettes and e-cigarettes call state tobacco quitlines in the U.S. each year. METHODS: This paper describes a behavioral intervention for dual users of cigarettes and e-cigarettes designed to increase cigarette abstinence. It also presents baseline data from a randomized pilot comparing the Enhanced E-cigarette Coaching (EEC) intervention with quitline treatment as usual (TAU). Oklahoma Tobacco Helpline callers were recruited at registration and randomized to EEC (n = 46) or TAU (n = 50). Treatment included 5 coaching calls and free nicotine replacement therapy (NRT). EEC treatment included enhanced e-cigarette assessment, education, a shared decision-making quit plan development approach, and tailored behavioral support. RESULTS: Participants averaged 40.6 years of age and 19.2 cigarettes per day; 85% smoked daily, 48% vaped daily, and 53% reported medium to high e-cigarette dependence. Most reported using e-cigarettes to quit (43%) or to cut down (26%) on smoking. Most had previously tried to quit smoking (91%) and had tried FDA-approved cessation medications (79%). Beliefs about vaping, NRT, and smoking included misinformation. After discussing the relative risks of NRT, vaping, and smoking, most EEC participants (89%) selected a quit plan that incorporated both NRT and vaping. CONCLUSIONS: At baseline, most participants reported a history of failed quit attempts with NRT and were vaping to quit or cut down on smoking, but they may need more support to completely quit smoking. If the EEC improves smoking outcomes, it would provide needed guidance on behavioral support best practices for individuals who vape and want to quit smoking.

Synthetic fluorescent MYC probe: Inhibitor binding site elucidation and development of a high-throughput screening assay.

We report the discovery of a fluorescent small molecule probe. This probe exhibits an emission increase in the presence of the oncoprotein MYC that can be attenuated by a competing inhibitor. Hydrogen-deuterium exchange mass spectrometry analysis, rationalized by induced-fit docking, suggests it binds to the "coiled-coil" region of the leucine zipper domain. Point mutations of this site produced functional MYC constructs resistant to inhibition in an oncogenic transformation assay by compounds that displace the probe. Utilizing this probe, we have developed a high-throughput assay to identify MYC inhibitor scaffolds. Screening of a diversity library (N = 1408, 384-well) and a library of pharmacologically active compounds (N = 1280, 1536-well) yielded molecules with greater drug-like properties than the probe. One lead is a potent inhibitor of oncogenic transformation and is specific for MYC relative to resistant mutants and transformation-inducing oncogenes. This method is simple, inexpensive, and does not require protein modification, DNA binding, or the dimer partner MAX. This assay presents an opportunity for MYC inhibition researchers to discover unique scaffolds.

Making Implementation Last: The Impact of Training Design on the Sustainability of an Evidence-Based Treatment in a Randomized Controlled Trial.

Although advances have been made in facilitating the implementation of evidence-based treatments, little is known about the most effective way to sustain their use over time. The current study examined the sustainability of one evidence-based treatment, Parent-Child Interaction Therapy (PCIT), following a statewide implementation trial testing three training methods: Cascading Model, Learning Collaborative, and Distance Education. Participants included 100 clinicians and 50 administrators from 50 organizations across Pennsylvania. Clinicians and administrators reported on sustainability at 24-months, as measured by the number of clients receiving PCIT and the continued use of the PCIT protocol. Multi-level path analysis was utilized to examine the role of training on sustainability. Clinicians and administrators reported high levels of sustainability at 24-months. Clinicians in the Cascading Model reported greater average PCIT caseloads at 24-months, whereas clinicians in the Learning Collaborative reported greater full use of the PCIT protocol at 24-months. Attending consultation calls was associated with delivering PCIT to fewer families. Implications for the sustainable delivery of PCIT beyond the training year as well as for the broader field of implementation science are discussed.

Subarachnoid haemorrhage rules in the decision for acute CT of the head: external validation in a UK cohort.

BACKGROUND: The Ottawa subarachnoid haemorrhage (SAH) rule and the Emerald SAH rule are clinical decision tools to aid in the decision for computed tomography (CT) of the head in patients attending an emergency department (ED) with acute non-traumatic headache. The objective of this study was to analyse the performance of these rules in a contemporary UK cohort. METHODS: We performed a retrospective external validation study. Patients undergoing CT of the head for the evaluation and treatment of non-traumatic headaches over a 6-month period in the ED at two tertiary centres were assessed. Each patient's Ottawa rule and Emerald rule were calculated and compared with their final diagnosis. RESULTS: The cohort consisted of 366 patients and there were 16 cases of SAH (based on CT findings or the presence of xanthochromia in cerebrospinal fluid). The Ottawa rule identified 288 patients requiring CT of the head. The sensitivity of the Ottawa rule was 100% (95% confidence interval (CI) 71-100%) and the specificity was 22% (95% CI 18-27%). The Emerald rule identified 267 patients who required CT, and achieved a sensitivity of 81% (95% CI 54-96%) and a specificity of 27% (95% CI 23-32%). CONCLUSIONS: The Ottawa SAH rule correctly identified all patients with SAH in this contemporary cohort. The Emerald rule did not perform as well in this cohort and is unsuitable for clinical use. The Ottawa rule is a useful tool to aid in the decision for CT of the head in patients presenting with acute non-traumatic headache to the ED.