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Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-β, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.

Dialectical behavior therapy (DBT) is an effective intervention for treating adults with emotional and behavioral dysregulation. The National DBT Project, Ireland was established in 2013 to coordinate the implementation of DBT across public community mental health settings at a national level. This study describes the implementation and evaluation of DBT across multiple independent sites in adult mental health services (AMHS). The Consolidated Framework for Implementation Research was used to guide this national implementation where barriers and facilitators to DBT implementation were considered. Nine AMHS teams completed DBT training and delivered the standard 12-month program. One hundred and ninety-six adults with borderline personality disorder participated in the program, and outcome measures were recorded at four time points. Significant reductions on outcome measures, including frequency of self-harm and suicidal ideation, were observed. This study highlights that DBT can be successfully implemented in community mental health settings as part of a coordinated implementation.

Respiratory failure is presumptively caused by microvascular thrombosis in some patients with coronavirus disease 2019 (COVID-19) requiring therapeutic anticoagulation. Anticoagulation treatment may cause life-threatening bleeding complications such as retroperitoneal hemorrhage. To the best of our knowledge, we report first case of a COVID-19 patient treated with therapeutic anticoagulation resulting in psoas hematoma due to lumbar artery bleeding. A 69-year-old patient presented with fever, malaise and progressive shortness of breath to our hospital. He was diagnosed with COVID-19 by RT-PCR. Due to an abnormal coagulation profile, the patient was started on enoxaparin. Over the course of hospitalization, the patient was found to have hypotension with worsening hemoglobin levels. Computed tomography scan of the abdomen and pelvis revealed a large psoas hematoma. Arteriogram revealed lumbar artery bleeding which was treated with embolization. Anticoagulation therapy, while indicated in COVID-19 patients, has its own challenges and guidelines describing dosages and indications in this disease are lacking. Rare bleeding complications such as psoas hematoma should be kept in mind in patients who become hemodynamically unstable, warranting prompt imaging for diagnosis and treatment with arterial embolization, thus eliminating need of surgical intervention.

BackgroundQualitative research in the area of DBT is limited, particularly at follow-up. The current study explored the follow-up experiences of individuals who previously received a diagnosis of borderline personality disorder and self-report having benefitted from DBT at the time of treatment.MethodsIndividuals who completed 12 months of standard DBT and were a minimum of two years post-completion were recruited. Individual semi-structured interviews were completed with a total of twelve participants.ResultsA thematic analysis generated three main themes which indicated that participants found DBT had a positive impact on their lives in the years after the programme and enabled further development; gave them control over their lives and the ability to manage setbacks and difficult situations; and contributed to healthier and more meaningful relationships with others.ConclusionsThe findings of this study indicated that DBT contributed positively to the participants’ lives and helped advance their recovery in the years after the programme.Despite the positive impact of DBT, participants required further support in the years following the intervention. Clinical and research implications of these findings are discussed.

This study assessed the prevalence of radix entomolaris and 2 canals at the distal aspect of mandibular first molars among different geographic regions by means of cone-beam computed tomographic imaging.Precalibrated observers from 23 worldwide geographic locations followed a standardized screening protocol to assess 5750 cone-beam computed tomographic images of mandibular first molars (250 per region), gathering demographic data and recording the presence of radix entomolaris and a second canal at the distal aspect of teeth. Intra- and interrater reliability tests were conducted and comparisons among groups were performed using proportions and odds ratio forest plots. The significance level was set at 5%.The results of intra- and interrater tests were above 0.79. The prevalence of radix entomolaris varied from 0.9% in Venezuela (95% confidence interval [CI], 0%-1.9%) to 22.4% in China (95% CI, 17.2%-27.6%). Regarding the proportion of a second distal canal, it ranged from 16.4% in Venezuela (95% CI, 11.8%-21.0%) to 60.0% in Egypt (95% CI, 53.9%-66.1%). The East Asia subgroup was associated with a significantly higher prevalence of an extra distolingual root, whereas the American subgroup, the American native ethnic group, and elderly patients were linked to significantly lower percentages of a second canal at the distal aspect of teeth. No significant differences were noted between male or female patients.The overall worldwide prevalence rates of radix entomolaris and a second canal at the distal aspect of the mandibular first molar were 5.6% and 36.9%, respectively. The East Asia geographic region and Asian ethnic group had a higher prevalence of a second distal root.

This paper investigates the cost-effectiveness of dialectical behaviour therapy (DBT) for treating individuals with borderline personality disorder (BPD) in a community setting in Ireland, in the short term. Resource utilisation and effectiveness data were collected as part of the National DBT Project, Ireland, and are incorporated into a cost-effectiveness analysis. The perspective taken was that of the service provider and payer. Direct health resources were included and effectiveness was measured using the EQ-5D-5L questionnaire. To examine cost-effectiveness, incremental costs are compared with incremental quality-adjusted life years, to estimate an incremental cost-effectiveness ratio. A probabilistic sensitivity analysis was employed to investigate parameter uncertainty. Scenario analyses are employed to investigate cost-effectiveness of DBT with varying assumptions around effectiveness and costs. The baseline analysis reveals that DBT is more expensive and more effective than routine clinical care (without DBT). The low incremental cost-effectiveness ratio suggests DBT can be considered cost effective in the short term. In each scenario analyses considered, the probability that DBT is cost effective is greater than 50%. Mental health care provision, including that of DBT, varies across jurisdictions, necessitating economic evaluations of current practice in community-based services, on a country-by-country basis, to inform resource allocation decisions. In line with previous research, the analysis here indicates DBT can be considered cost effective in the short term. Future data collection on alternative comparators and long-term outcomes associated with DBT is warranted to investigate the longer term cost-effectiveness of DBT.

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.

The presence of multiple root canals is an important morphologic aspect of mandibular premolars. This study aimed to perform a worldwide analysis on the prevalence of a lingual canal in mandibular premolars and to evaluate its influence on patients' demographics in 23 countries using cone-beam computed tomographic images.Observers from 23 countries were instructed to evaluate cone-beam computed tomographic images of 300 first and 300 second premolars (13,800 teeth) regarding the presence of a lingual canal, canal configuration, and data related to patients' ethnicity, age, and sex following a standardized screening methodology. Intra- and interrater evaluations were performed using the Cohen kappa test and intraclass correlation coefficient. Proportion and odds ratio forest plots were calculated in order to compare groups. Statistical significance was set at 5%.Both kappa and intraclass correlation coefficient values were above 0.60, and the percentage of agreement was 94.9% (first premolar) and 97.8% (second premolar). A significant statistical difference was observed between the worldwide proportion of a lingual canal in mandibular first (23.8%; range, 12.0%-32.7%) and second (5.3%; range, 1.0%-15.3%) premolars (P.05). Asians and patients over 60 years old were associated with the lowest proportions of a lingual canal (P.05), whereas Africans and younger groups were associated with the highest proportions (P.05). The prevalence of a lingual canal in males (27.9%) was higher than females (20.0%) for the first premolar only (P.05). Males were associated with 1.533 and 1.597 higher odds of presenting a lingual root canal in the first and second premolars, respectively.The worldwide proportion of a lingual root canal was 23.6% and 5.3% for the first and second premolars, respectively. Ethnicity, geographic region, age, and sex had an influence on the outcomes.

Background: Novel coronavirus 2019 (COVID-19) has been the focus of the medical world since being declared a pandemic in March 2020. While the pathogenesis and heterogeneity of COVID-19 manifestations is still not fully understood, viral evasion of cellular immune responses and inflammatory dysregulation are believed to play essential roles in disease progression and severity. Case Presentation: We present the first case of a patient with COVID-19 with massive pulmonary embolism treated successfully with systemic thrombolysis, VA-ECLS, and bail out catheter directed thrombolysis. He was discharged from the hospital after an eventful hospital course on therapeutic anticoagulation with warfarin. Conclusions: We present the first case of a patient with COVID-19 with massive pulmonary embolism (PE) treated successfully with systemic thrombolysis, VA-ECLS and bail out catheter directed thrombolysis. In our experience catheter directed thrombolysis comes with an acceptable bleeding risk despite use of mechanical circulatory support, particularly with meticulous attention to vascular access and dose response monitoring.

Gray zone lymphoma, also known as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, is a rare malignancy with overlapping features of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Most commonly mediastinal involvement is seen. Extranodal involvement is rare. In this case report, we present the case of a 59-year-old male who presented with stress-related left shoulder pain, ultimately diagnosed with gray zone lymphoma. The patient was treated with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin-rituximab (EPOCH-R) regimen followed by consolidation radiotherapy resulting in complete response. We are highlighting this case as rare and atypical presentation of a rare disease.

Dialectical behaviour therapy (DBT) is an intervention with demonstrated efficacy and effectiveness for individuals with borderline personality disorder. In recent years, research has shifted focus to the evaluation of DBT implementation in routine clinical settings. In this article, we consider the empirical evidence that guides clinicians and managers in health services with local implementation of DBT in community settings. Research on this topic has most recently advanced to the evaluation of coordinated implementation efforts. Although coordinated implementation has merit, it does not mitigate all implementation challenges. Consideration of implementation facilitators and barriers in DBT can also be applied to other evidence-based interventions for BPD and for adaptations for individuals with early-stage symptomatology. Ongoing research and evaluation in these areas is recommended.

BACKGROUND Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. Previous studies have reported on varying lengths of treatment, however, and optimal treatment duration has not yet been identified. While the treatment developers initially proposed a 16-week programme, they have more recently recommended an extension to 24 weeks. This study compares outcomes for adolescents and parent/guardians who participated in 16- and 24-week DBT-A programmes in a community setting. METHODS Eighty-four adolescents and 100 parent/guardians participated in 16-week DBT-A, while 68 adolescents and 67 parent/guardians participated in the 24-week programme. Outcome measures for adolescents included the presence and frequency of self-harm, suicidal ideation and depression; and for parents were burden, grief and parental stress. Outcomes were assessed at pre- and postintervention. Linear mixed-effects models were used to estimate the treatment duration effect (24-week vs. 16-week) utilising all available data at pre- and postintervention. RESULTS Data analyses showed a reduction in the presence and frequency of self-harm at postintervention for adolescents in both programmes. Both adolescent and parent participants in the 16- and 24-week programmes also showed changes indicating significant improvement on all self-report outcome measures (p

Background Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. This study describes the implementation and effectiveness of 16-week DBT-A across multiple sites in publicly funded child/adolescent mental health services (CAMHS) in Ireland. Method The Consolidated Framework for Implementation Research was used to guide this national implementation. Fifty-four clinicians from seven CAMHS teams completed DBT training and delivered the 16-week DBT-A programme. Eighty-four adolescents with emotional and behavioural dysregulation participated in the intervention and outcome measures were administered at preintervention, postintervention and 16-week follow-up. Results Significant reductions on all outcome measures were observed for DBT-A participants including presence and frequency of self-harm, suicidal ideation and depression. Reductions in the number of acute inpatient admissions, bed days and emergency department visits were also reported. Conclusions DBT-A can be successfully implemented in CAMHS settings and yield positive outcomes for adolescents with emotional and behavioural dysregulation.

Six synthetic head models wearing ballistic protective helmets were used to recreate two military combat-related shooting incidents (three per incident, designated ‘Incident 1’ and ‘Incident 2’). Data on the events including engagement distances, weapon and ammunition types was collated by the Defence Science and Technology Laboratory. The models were shot with 7.62 × 39 mm ammunition downloaded to mean impact velocities of 581 m/s (SD 3.5 m/s) and 418 m/s (SD 8 m/s), respectively, to simulate the engagement distances. The damage to the models was assessed using CT imaging and dissection by a forensic pathologist experienced in reviewing military gunshot wounds. The helmets were examined by an MoD engineer experienced in ballistic incident analysis. Damage to the helmets was consistent with that seen in real incidents. Fracture patterns and CT imaging on two of the models for Incident 1 (a frontal impact) were congruent with the actual incident being modelled. The results for Incident 2 (a temporoparietal impact) produced realistic simulations of tangential gunshot injury but were less representative of the scenario being modelled. Other aspects of the wounds produced also exhibited differences. Further work is ongoing to develop the models for greater ballistic injury fidelity.

Objectives: Previous research indicates that dialectical behaviour therapy for adolescents (DBT-A) is effective in treating emotionally dysregulated adolescents with self-harm and/or suicidal ideation. As part of the DBT-A programme, parents attend the weekly skills group with their child. However, few studies have evaluated parental outcomes in DBT-A. This multi-site study aims to explore the outcomes and experiences of parents who participated in a 16-week DBT-A programme in Ireland. Methods: This study was conducted in community-based child and adolescent mental health services (CAMHS) in the national public health system in Ireland. Participants were parent/guardians of adolescents attending a DBT-A programme in their local CAMHS. Participants attended the group skills component of the DBT-A programme. This study utilised a mixed methods approach where both quantitative and qualitative data were collected from participants. Self-report measures of burden, grief and parental stress were completed at pre-intervention, post-intervention and 16-week follow-up. Qualitative written feedback was obtained at post-intervention. The data were analysed using multi-level linear mixed-effects models and content analysis. Results: One hundred participants (76% female) took part in this study. Significant decreases were reported for objective burden, subjective burden, grief and parental stress from pre- to post-intervention (p < 0.01). Participants reported that the skills component of DBT-A was useful in meeting their own needs and the needs of their child. Discussion: DBT-A shows promise for parents as well as their adolescent child. Future studies should evaluate changes to family relationships following completion of the programme and also include controlled comparison groups.

Background: The implementation of evidence-based interventions for borderline personality disorder in community settings is important given that individuals with this diagnosis are often extensive users of both inpatient and outpatient mental health services. Although work in this area is limited, previous studies have identified facilitators and barriers to successful DBT implementation. This study seeks to expand on previous work by evaluating a coordinated implementation of DBT in community settings at a national level. The Consolidated Framework for Implementation Research (CFIR) [1] provided structural guidance for this national level coordinated implementation. Methods: A mixed methods approach was utilised to explore the national multi-site implementation of DBT from the perspective of team leaders and therapists who participated in the coordinated training and subsequent implementation of DBT. Qualitative interviews with DBT team leaders (n = 8) explored their experiences of implementing DBT in their local service and was analysed using content analysis. Quantitative surveys from DBT therapists (n = 74) examined their experience of multiple aspects of the implementation process including orienting the system, and preparations and support for implementation. Frequencies of responses were calculated. Written qualitative feedback was analysed using content analysis. Results: Five themes were identified from the interview data: team formation, implementation preparation, client selection, service level challenges and team leader role. Participants identified team size and support for the team leader as key points for consideration in DBT implementation. Key challenges encountered were the lack of system support to facilitate phone coaching and a lack of allocated time to focus on DBT. Implementation facilitators included having dedicated team members and support from management. Conclusions: The barriers and facilitators identified in this study are broadly similar to those reported in previous research. Barriers and facilitators were identified across several domains of the CFIR and are consistent with a recently published DBT implementation Framework [2]. Future research should pay particular attention to the domain of characteristics of individuals involved in DBT implementation. The results highlight the importance of a mandated service plan for the coordinated implementation of an evidence-based treatment in a public health service.Trial Registration: ClinicalTrials.gov ID: NCT03180541; Registered June 7th 2017 ‘retrospectively registered’

Background Dialectical behaviour therapy (DBT) is an evidence-based intervention for borderline personality disorder (BPD) but is an intensive treatment with significant health service costs. Access to DBT can sometimes be restricted due to limited resources. Positive results have been reported for the use of DBT skills training (DBT-ST), one of the four modes of standard DBT, in the treatment of individuals with BPD who self-harm. This study evaluates DBT-ST for a subgroup of individuals attending community mental health services who may have a diagnosis of BPD (or emerging BPD traits) but who are not actively self-harming. Methods Participants in this study were 100 adults attending community mental health services with a diagnosis of BPD, emerging BPD traits or emotion dysregulation who were not actively self-harming. The majority of participants were female (71%), aged 25–34 years (32%), single (48%) and unemployed (34%). Participants partook in a 24-week DBT-ST intervention delivered by DBT therapists. Outcome measures included the Difficulties in Emotion Regulation Scale (DERS), the DBT Ways of Coping Checklist (DBT-WCCL) and the Five Facet Mindfulness Questionnaire (FFMQ). Measures were administered at pre-intervention, at the end of each skills module, and at post-intervention. Results Significant reductions in emotion dysregulation (DERS) and dysfunctional coping (DBT-WCCL) scores were reported from pre- to post-intervention (p p Discussion The results of this uncontrolled study suggest that a standalone 24-week DBT-ST intervention may have a beneficial impact in terms of a reduction in emotion dysregulation and dysfunctional coping, and an increase in mindfulness and DBT skills use in patients with BPD/ emerging BPD traits who are not currently engaging in self-harm. Adequately powered randomised controlled trials are required to determine treatment efficacy in comparison to standard DBT for this population.

Background Mechanistic data and results from a limited number of cross-sectional epidemiologic studies have suggested a possible link between phthalates and adverse cardiovascular outcomes. Objective To evaluate the association between urinary levels of eight phthalate metabolites and subsequent risk of cardiovascular death in a prospective cohort analysis. Methods We identified 5080 individuals 40 years or older who participated in the continuous National Health and Nutrition Examination Survey (NHANES) from 1999 to 2008 and who had measured phthalate levels available. We a priori excluded individuals in later cycles of NHANES with measured phthalates so as to have the potential of at least three years of follow-up time on all members of the cohort. Questionnaire, exam and laboratory data were merged with a public access NHANES mortality file updated through December 31, 2011. The associations between cardiovascular death and quartile levels of the phthalate metabolites were investigated using Cox proportional hazard models. Results There were 175 deaths due to cardiovascular disease deaths over a mean of 7.0 years of follow-up. No association between cardiovascular disease mortality and individual urinary phthalate metabolites was observed. After adjustments, hazard ratios comparing the highest to lowest quartile ranged from 0.73 (95%CI: 0.5–1.2) for mono-ethyl phthalate [MEP] to 1.4 (95%CI:0.8–2.5) for mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP]. Conclusions Urinary levels of phthalate metabolites were not associated with increased cardiovascular disease mortality. Additional larger cohort studies with longer follow-up focused on cardiovascular disease incidence are needed.

The unsaturated flow of water in soil through unstable wetting fronts has been documented in literature. These instabilities can lead to the development of finger-flow profiles, whose paths can be “remembered” by a solid matrix of soil during future infiltration even after periods of desaturation. This process has been modelled for a 1D column of soil by the Richards equation, a non-equilibrium relaxation ODE, and Preisach hysteresis, all of which are required for finger flow. In this paper a comparison is made to similar work that use Parlange’s model of hysteresis and show that similar results are achieved by instead including the Preisach model. In addition, the model allows for the strength of hysteresis to be changed by a single parameter thus allowing the potential of parameter fitting of data in the future.

Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta. The link to possible changes in gross structure was also analyzed. For this purpose, fresh and 20 h-cultured aortic arterial segments from intact and orchidectomized rats were used to analyze: (i) the release and vasomotor effect of the thromboxane A2 (TXA2), prostaglandin (PG) E2, PGF2α and PGI2; (ii) the vasodilator response induced by acetylcholine (ACh) as well as the involvement of prostanoids, in particular TXA2, in the ACh-induced response; (iii) the effect of activation of thromboxane/prostaglandin (TP) receptors on the ACh-induced response; and (iv) the vascular structure. The results showed that organ culture: i) increased production of prostanoids; ii) increased prostanoids-induced vasomotor responses; iii) decreased ACh-induced relaxation after incubation with indomethacin, a blocker of cyclooxygenases; iv) increased the ACh-induced relaxation after incubation with the TXA2 synthase inhibitor, furegrelate, more in arteries from orchidectomized rats than in those of intact rats; v) diminished ACh-induced relaxation after U-46619 incubation only in arteries from orchidectomized rats; and vi) preserved the integrity of the different vascular layers. These results showed the protective role of male sex hormones against the induced vascular damage, since a decreased deleterious effect of prostanoids, in particular that of TXA2, was observed in arteries from rats with intact gonadal function.

Background Whole school approaches to mental health are recommended where schools and community partners work together to support positive mental health for young people. Universal interventions which adopt this approach are limited however. This study evaluates the pilot implementation of DBT STEPS-A, a social-emotional learning programme for adolescents, in Ireland. Method Data were collected at the beginning and end of the academic year from students who participated in DBT STEPS-A and a control group. A matched comparison was conducted where a subset of the data was analysed consisting of 72 adolescents aged 15-16 years from two schools in the south of Ireland. Outcomes included emotion symptoms, dysfunctional coping and DBT skill use. Linear mixed-effects models were used to estimate the treatment effect (intervention vs. control). Results A statistically significant treatment effect was observed on two of four outcome measures (emotion symptom index: p = 0.011; internalising problems: p = 0.012). The effect sizes were large (Cohen's F squared = 0.65 and 0.83 respectively). Conclusions Significant reductions on measures which assess constructs including depression, anxiety and social stress were found for the intervention group. The results suggest that DBT STEPS-A may yield positive effects for adolescents who complete the intervention. Feedback from adolescents and teachers suggests that refinement of content, structure and implementation may make the programme more accessible to an adolescent population.

The National Dialectical Behaviour Therapy (DBT) Project, Ireland was established in 2013 in the Republic of Ireland. The aims of the project were twofold: to implement DBT in Community Mental Health Services across Ireland and to evaluate this coordinated implementation of DBT at a national level. This chapter describes the process of implementing DBT in the public health system in Ireland. It first describes how the need emerged for a coordinated national implementation, and the framework put in place to establish and put this coordinated initiative into action. It then considers challenges to a national implementation of an evidence-based treatment such as DBT and approaches that were employed to overcome such challenges. The chapter concludes with a summary of implementation outcomes and key learnings from this initiative as well as recommendations and considerations for DBT implementation and ongoing sustainability in community mental health services.

Triple negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers and is more likely to affect younger women, women of African American descent, and BRCA1 mutation carriers. TNBC is typically an aggressive cancer and is defined as the absence of positive staining for estrogen (ER) and progesterone (PR) receptor, and a lack of amplification of HER2. Due to its receptor status, TNBC is insensitive to the conventional targeted treatment utilized in ER/PR/HER2 positive breast cancer leading to poor prognosis and early visceral metastasis with survival rates for women who relapse within 5 years of treatment being significantly lower than hormone receptor positive breast cancer. Therefore, understanding the mechanisms that drive the formation of TNBC can aid in determining targets to develop better treatment options. We investigated differences in the tumor microenvironment between TNBC and ER positive breast cancer patient tissue samples. Hematoxylin & eosin stain of invasive ductal carcinomas revealed that TNBC patients had higher amounts of tumor infiltrating leukocytes compared to ER positive breast cancers. In premalignant breast cancer patients, ER negative ductal carcinoma in situ (DCIS) patients had significantly higher infiltrating leukocytes compared to ER positive DCIS indicating that inflammation may be a contributing factor in TNBC. Research on molecular profiling of TNBC has revealed that a subset of gene expression patterns are associated with the basal-myoepithelial cells rather than the luminal cells, however, previous evidence indicates that TNBC arises from luminal progenitors which undergo an abnormal conversion to basal-like progenitors with enhanced growth and survival promoting characteristics. We propose this conversion occurs due to the presence of inflammatory signals early in tumor development which trigger a cascade of events that leads to acquisition of a basal-like phenotype in luminal progenitor cells and upregulation of stem-like properties, resulting in the formation of basal-like breast cancer/TNBC. Treatment of non-malignant breast epithelial cells with IL-6 increased sphere-forming efficiency under stem cell growth promoting conditions and an inhibitor of the IL-6/STAT3 pathway decreased ALDH enzymatic activity as measured by Aldefluor assay. Also, treatment with IL-6 downregulated the luminal marker, epithelial specific antigen (ESA), and increased the expression of the myoepithelial marker, CD49f, on the cell surface of non-malignant breast epithelial cells, indicating an increase in the basal-like cell population and a loss of the luminal cell population. Therefore, inflammation appears to be a common feature in TNBC compared to ER positive breast cancer and the presence of an inflammatory stimulus in the breast may promote the conversion of luminal to basal-like cells, promoting the upregulation of stem-like properties and development of TNBC. These data suggest that anti-inflammatory drugs could potentially be used to inhibit these events from occurring in the development of TNBC, leading to decreased tumor growth and better treatment options. Citation Format: Jennifer Sims-Mourtada, Kimberly M Arnold, Lynn Opdenaker, Daniel Flynn. Inflammation promotes stem-like characteristics and increases stemness of breast epithelial cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-09.

Pain physiology education is an important component in the management of patients with chronic musculoskeletal pain. The Neurophysiology of Pain Questionnaire (NPQ) was developed in English to assess pain physiology knowledge in patients. This study aimed to translate the NPQ into French (NPQ-Fr) and to investigate the main psychometric properties of the NPQ-Fr. The translation was performed using the best practice translation guidelines. One hundred and one French-speaking patients with chronic non-specific spinal pain completed the NPQ-Fr to assess its acceptability and presence of floor/ceiling effects and test its dimensionality. The construct validity was tested by comparing the patients NPQ-Fr scores to those of 17 physiotherapists and investigating its correlation with subscales of the Short Form-36 questionnaire. The reliability (i.e., internal consistency and test-retest reliability) was also investigated. To test the test-retest reliability, 70 patients were asked to complete the NPQ-Fr twice with one week in between. Regarding the NPQ-Fr psychometric properties: 1) acceptability was good; 2) internal consistency reached a Cronbach α-coefficient of 0.44; 3) no floor and ceiling effects were observed in patients; 4) a principal factor analysis generated three major factors; 5) construct validity was good; and 6) reliability was acceptable (intraclass correlation coefficient = 0.644; standard error of measurement = 1.5). The NPQ-Fr has satisfactory basic psychometric properties in patients with chronic spinal pain.

Background Dialectical behaviour therapy (DBT) is noted to be an intervention with a growing body of evidence that demonstrates its efficacy in treating individuals diagnosed with borderline personality disorder (BPD). Evidence for the effectiveness of DBT in publicly funded community mental health settings is lacking however. No study to our knowledge has been published on the effectiveness of a 12 month standard DBT programme without adaptations for individuals with BPD in a publicly funded community mental health setting and no study has included data across multiple time-points. The main objective of the current study was to determine if completion of a 12 month DBT programme is associated with improved outcomes in terms of borderline symptoms, anxiety, hopelessness, suicidal ideation, depression and quality of life. A secondary objective includes assessing client progress across multiple time-points throughout the treatment. Methods Fifty-four adult participants with BPD completed the standard DBT programme across four sites in community mental health settings in the Republic of Ireland. Data was collected by the DBT therapists working with participants and took place at 8 week intervals across the 12 month programme. To explore the effects of the intervention for participants, linear mixed-effects models were used to estimate change utilising data available from all time-points. Results At the end of the 12 month programme, significant reductions in borderline symptoms, anxiety, hopelessness, suicidal ideation and depression were observed. Increases in overall quality of life were also noted. In particular, gains were made during the first 6 months of the programme. There was a tendency for scores to slightly regress after the six-month mark which marks the start of the second delivery of the group skills cycles. Conclusions The current study provides evidence for the effectiveness of standard DBT in publicly funded community mental health settings. As participants were assessed at the end of every module, it was possible to observe trends in symptom reduction during each stage of the intervention. Despite real-world limitations of applying DBT in community settings, the results of this study are comparable with more tightly controlled studies. Trial registration ClinicalTrials.gov ID: NCT03166579; Registered May 24th 2017 ‘retrospectively registered’ Electronic supplementary material The online version of this article (doi:10.1186/s40479-017-0070-8) contains supplementary material, which is available to authorized users.

Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able torepopulatethetumor.TheHedgehog(HH)signaling pathway hasbeen shown toregulate theproliferation andsurvivalofbreastcancerstemcells,andhasbeenshowntopromoteresistancetochemotherapythroughtheactivationof multi-drug resistance and pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4–24h after DOC treatment. This activation had little effect on the bulkof the tumor cell population as inhibition of HH signaling failedto increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemnessmarkersaswellasmammosphereformationwereobservedaftertreatmentwithDOCsuggestinganincreaseinthe breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced byDOC treatmentdoesnot haveachemosensitizing effectontheheterogeneoustumorpopulation,butmayberequiredfor survival and expansion of breast cancer stem cells after chemotherapy. © 2014 Wiley Periodicals, Inc.

Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.The aim was to identify underlying genetic causes of short stature with advanced bone age.We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1GA), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064TC) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.

Vincent Tinto originally asserted, “… it is the individual’s integration into the academic and social systems of the college that most directly related to his continuance in that college” (Tinto, Review of Educational Research 45(10): 89–125, 1975), yet the rates of college degree attainment are still stagnant. Institution-level research on student engagement indicates that both types of engagement contribute to increased student persistence and degree attainment. Research has prompted going beyond institutional-level data and calls for using of nationally representative, longitudinal data to addressing engagement. Using the 2004/09 Beginning Postsecondary Students Longitudinal Study (BPS:04/09) and logistic regression, this study finds that both academic and social student engagement behaviors significantly impact degree attainment in postsecondary education net of individual and institutional factors. Interaction analysis of the two different types of engagement finds that the impact is not additive but instead is differential and dependent upon the student’s engagement typology as proposed by Coates (Assessment and Evaluation in Higher Education 32(2): 121–141, 2007).

Introduction The aim of this study was to evaluate and compare the C-shaped mandibular second molar prevalence in different regions around the world with the aid of cone-beam computed tomography technology. Methods Nine field observers from 9 different geographic regions were calibrated. A total of 400 samples were collected in each region. The prevalence of C-shaped anatomy was calculated. The number of roots and the configuration of the C-shaped canals at 3 different axial levels were also evaluated. The z -test was used to analyze the difference between the means of each independent group. Intrarater reliability was also tested. Results A total of 3600 teeth from 2735 patients were included in this research; 499 teeth presented C-shaped root canal configuration, representing a global prevalence of 13.9%. China had a prevalence of 44.0%, which was significantly higher than any other region. The C-shape prevalence in women was 16.5%, which was significantly higher than the 10.4% prevalence found in men. No difference between sides (37 or 47) was evident in the global sample. Conclusions Cone-beam computed tomography is a valuable tool to evaluate the C-shaped root canal configuration in vivo . In the present study, China presented the highest prevalence of C-shaped mandibular second molars when compared with other regions. Women exhibited a higher prevalence than men.

Wireless electroencephalography (EEG) of small animal subjects typically utilizes miniaturized EEG devices which require a robust recording and electrode assembly that remains in place while also being well-tolerated by the animal so as not to impair the ability of the animal to perform normal living activities or experimental tasks. We developed simple and fast electrode assembly and method of electrode implantation using electrode wires and wire-wrap technology that provides both higher survival and success rates in obtaining recordings from the electrodes than methods using screws as electrodes. The new wire method results in a 51% improvement in the number of electrodes that successfully record EEG signal. Also, the electrode assembly remains affixed and provides EEG signal for at least a month after implantation. Screws often serve as recording electrodes, which require either drilling holes into the skull to insert screws or affixing screws to the surface of the skull with adhesive. Drilling holes large enough to insert screws can be invasive and damaging to brain tissue, using adhesives may interfere with conductance and result in a poor signal, and soldering screws to wire leads results in fragile connections. The methods presented in this article provide a robust implant that is minimally invasive and has a significantly higher success rate of electrode implantation. In addition, the implant remains affixed and produces good recordings for over a month, while using economical, easily obtained materials and skills readily available in most animal research laboratories.

Introduction Compte tenu de l’existence repandue des croyances deleteres relatives au mal de dos [1] ; [2] et des limites des questionnaires existant, le « back pain attitudes questionnaire (Back-PAQ) » a recemment ete developpe pour mieux les identifier [3]. L’objectif de cette etude etait de traduire en francais la version courte (10 items) de ce questionnaire et d’evaluer les qualites psychometriques de cette nouvelle version (le Back-PAQ-Fr). Materiel, population et methode Le processus de traduction a ete realise en respectant les differentes etapes decrites dans les recommandations internationales [4] (Figure 1). Le Back-PAQ-Fr a ete soumis a 105 patients presentant une lombalgie (LB), afin de rechercher la presence d’un eventuel effet plancher/plafond et d’examiner sa coherence interne. Pour examiner la validite de construit, les patients ont egalement ete soumis au « back beliefs questionnaire (BBQ) » et au « brief illness perception questionnaire (Brief IPQ) ». Enfin, 55 patients ont ete invites a completer a nouveau le Back-PAQ-Fr une semaine plus tard (re-test) pour examiner sa reproductibilite. Resultats Les patients etaient âges en moyenne de 45,3 ans et 71 % d’entre eux souffraient de LB chronique. Seuls 2 patients n’ont pas complete tous les items du questionnaire. L’analyse des scores totaux minimum et maximum n’a indique aucun effet plancher/plafond. Le coefficient alpha de Cronbach caracterisant la coherence interne du questionnaire etait 0,54. De facon attendue, l’etude de validite a confirme l’existence de correlations significatives entre les scores BACK-PAQ-Fr et les scores aux questionnaires Brief IPQ (rho = 0,25, p

Maxillary first molar second mesiobuccal (MB2) root canal prevalence may change among different populations. The aim of this study was to analyze the worldwide prevalence of the MB2 root canal and understand its possible relation with sex, age, side, and root configuration using in vivo cone-beam computed tomographic (CBCT) assessment.Observers from 21 regions were calibrated to achieve a similar CBCT assessment methodology and instructed to collect data from 250 maxillary first molars in previously existing examinations. Intra- and interrater reliability tests were performed. The sample size included 5250 molars and was defined by way of a preliminary trial. Data collected included MB2 presence, sex, age, side, number of roots per tooth, and mesiobuccal root configuration. The z test for proportions in independent groups was used to analyze the differences among subgroups. P .05 was considered significant.The worldwide CBCT-assessed MB2 prevalence was 73.8%, ranging from 48.0% in Venezuela to 97.6% in Belgium. The prevalence in males and females was 76.3% and 71.8%, respectively (P .05). Significantly higher MB2 proportions were found in younger patients and 3-rooted molar configurations. The group intraclass correlation coefficient and the percentage of agreement for the MB2 presence were 0.95 and 0.91, respectively. The intrarater Cohen kappa value was above 0.61 for all observers.MB2 prevalence in the analyzed regions varied widely. The differences may be associated with specificities within each region but also patient demographics. Males, younger patients, and 3-rooted configurations were associated with higher MB2 proportions.