Assessing practical implementation of modular psychotherapy for youth in community-based settings using benchmarking.

Background: Achieving high quality outcomes in a community context requires the strategic coordination of many activities in a service system, involving families, clinicians, supervisors, and administrators. In modern implementation trials, the therapy itself is guided by a treatment manual; however, structured supports for other parts of the service system may remain less well-articulated (e.g., supervision, administrative policies for planning and review, information/feedback flow, resource availability). This implementation trial investigated how a psychosocial intervention performed when those non-therapy supports were not structured by a research team, but were instead provided as part of a scalable industrial implementation, testing whether outcomes achieved would meet benchmarks from published research trials. Method: In this single-arm observational benchmarking study, a total of 59 community clinicians were trained in the Modular Approach to Therapy for Children (MATCH) treatment program. These clinicians delivered MATCH treatment to 166 youth ages 6 to 17 naturally presenting for psychotherapy services. Clinicians received substantially fewer supports from the treatment developers or research team than in the original MATCH trials and instead relied on explicit process management tools to facilitate implementation. Prior RCTs of MATCH were used to benchmark the results of the current initiative. Client improvement was assessed using the Top Problems Assessment and Brief Problem Monitor. Results: Analysis of client symptom change indicated that youth experienced improvement equal to or better than the experimental condition in published research trials. Similarly, caregiver-reported outcomes were generally comparable to those in published trials. Conclusions: Although results must be interpreted cautiously, they support the feasibility of using process management tools to facilitate the successful implementation of MATCH outside the context of a formal research or funded implementation trial. Further, these results illustrate the value of benchmarking as a method to evaluation industrial implementation efforts.Plain Language Summary: Randomized effectiveness trials are inclusive of clinicians and cases that are routinely encountered in community-based settings, while continuing to rely on the research team for both clinical and administrative guidance. As a result, the field still struggles to understand what might be needed to support sustainable implementation and how interventions will perform when brought to scale in community settings without those clinical trial supports. Alternative approaches are needed to delineate and provide the clinical and operational support needed for implementation and to efficiently evaluate how evidence-based treatments perform. Benchmarking findings in the community against findings of more rigorous clinical trials is one such approach. This paper offers two main contributions to the literature. First, it provides an example of how benchmarking is used to evaluate how the Modular Approach to Therapy for Children (MATCH) treatment program performed outside the context of a research trial. Second, this study demonstrates that MATCH produced comparable symptom improvements to those seen in the original research trials and describes the implementation strategies associated with this success. In particular, although clinicians in this study had less rigorous expert clinical supervision as compared with the original trials, clinicians were provided with process management tools to support implementation. This study highlights the importance of evaluating the performance of intervention programs when brought to scale in community-based settings. This study also provides support for the use of process management tools to assist providers in effective implementation.

Implementing Evidence Based Practices for Children's Mental Health: A Case Study in Implementing Modular Treatments in Community Mental Health.

There is strong enthusiasm for utilizing implementation science in the implementation of evidence-based programs in children's community mental health, but there remains work to be done to improve the process. Despite the proliferation of implementation frameworks, there is limited literature providing case examples of overcoming implementation barriers. This article examines whether the use of three implementations strategies, a structured training and coaching program, the use of professional development portfolios for coaching, and a progress monitoring data system, help to overcome barriers to implementation by facilitating four implementation drivers at a community mental health agency. Results suggest that implementation is a process of recognizing and adapting to both predictable and unpredictable barriers. Furthermore, the use of these implementation strategies is important in improving implementation outcomes.

Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Metástasis coroidea de cáncer de mama / Choroidal metastasis from breast cancer

No disponible

Tuberculosis intraocular / Intraocular tuberculosis

No disponible

Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome.

Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Across evolution, maternal care is a key source of environmental sensory signals to the developing brain, and a vast body of work has linked quantitative and qualitative aspects of maternal care to emotional outcome in children and animals. However, the fundamental properties of maternal signals, that promote advantageous vs pathological outcomes in the offspring, are unknown and have been a topic of intense study. We studied emotional outcomes of adolescent rats reared under routine or impoverished environments, and used mathematical approaches to analyze the nurturing behaviors of the dams. Unexpectedly, whereas the quantity and typical qualities of maternal care behaviors were indistinguishable in the two environments, their patterns and rhythms differed drastically and influenced emotional outcomes. Specifically, unpredictable, fragmented maternal care patterns translated into high-entropy rates of sensory signals to the offspring in the impoverished cages. During adolescence, these offspring had significant reductions in sucrose preference and in peer-play, two independent measures of the ability to experience pleasure. This adolescent anhedonia, often a harbinger of later depression, was not accompanied by measures of anxiety or helplessness. Dopaminergic pleasure circuits underlying anhedonia are engaged by predictable sequences of events, and predictable sensory signals during neonatal periods may be critical for their maturation. Conversely, unpredictability maternal-derived signals may disrupt these developmental processes, provoking anhedonia. In sum, high-entropy and fragmented patterns of maternal-derived sensory input to the developing brain predicts, and might promote, the development of anhedonia in rodents, with potential clinical implications.

Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics.

Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group.

Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations.

Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in ∼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3ca(H1047R)-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition.

The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

Transcrural coeliac plexus block simulated on 200 computed tomography images.

BACKGROUND: We previously reported a modified transcrural coeliac plexus block (tCPB) case, using parameters obtained from a pre-procedural computed tomography (CT) image of that patient for the subsequent tCPB under fluoroscopy. In this study, we performed the same tCPB simulation on 200 CT images to determine optimal needle placement parameters with a comparison to the classic technique. METHODS: On each CT image across the coeliac trunk, the tCPB was simulated on both sides with the needle trajectory placed between the vertebra and organs targeting the coeliac trunk. The distances of the needle entrance from the midline, the insertion angles, and depths were measured and analysed in the groups: laterality, gender, intra-abdominal condition, and coeliac-aortic-vertebral (c-a-v) distribution. RESULTS: Thirty placements failed to avoid organ penetration. The left-sided placements required a shorter distance, 3.58 (1.02) cm, with a steeper angle, 84.1° (6.0°), than those for the right placements [7.04 (1.56) cm, 61.1° (6.2°)] (P<0.00001). The shortest distances, 3.1 (0.8) cm, with the steepest angles, 87.7° (4.5°), were seen in the patients whose c-a-v distributions were left-left located (P<0.00001). Males required longer distance for needle insertion (P≤0.05). Cancer patients required a shorter distance with a steeper angle for the right needle placements (P<0.05). CONCLUSIONS: Needle placement parameters for tCPB vary in laterality, gender, pathologies, and c-a-v distributions. We would advocate a simulated block on individual patient's CT image to obtain relevant measurements for subsequent tCPB, although a clinical outcome study is warranted.

The Winning with Wellness pilot project: rural Appalachian elementary student physical activity and eating behaviors and program implementation 4 years later.

School-based efforts to promote physical activity and healthier eating are a potentially effective approach to decreasing child obesity in rural populations. This article describes follow-up data on student activity and eating behaviors 4 years after implementation of the Winning with Wellness obesity prevention initiative. This project was based on the Centers for Disease Control and Prevention's coordinated school health model and used a community-based participatory research approach to address health behaviors in rural Appalachian elementary students. Results suggest significant increases in daily pedometer steps and healthier food selections by students as well as teacher support for continued health promotion efforts.

Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes.

PURPOSE: To establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself. METHODS: Thirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures. RESULTS: Scores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures. DISCUSSION: Children with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.

Cancer diagnostic assessment programs: standards for the organization of care in Ontario.

BACKGROUND: Improving access to better, more efficient, and rapid cancer diagnosis is a necessary component of a high-quality cancer system. How diagnostic services ought to be organized, structured, and evaluated is less understood and studied. Our objective was to address this gap. METHODS: As a quality initiative of Cancer Care Ontario's Program in Evidence-Based Care, the Diagnostic Assessment Standards Panel, with representation from clinical oncology experts, institutional and clinical administrative leaders, health service researchers, and methodologists, conducted a systematic review and a targeted environmental scan of the unpublished literature. Standards were developed based on expert consensus opinion informed by the identified evidence. Through external review, clinicians and administrators across Ontario were given the opportunity to provide feedback. RESULTS: The body of evidence consists of thirty-five published studies and fifteen unpublished guidance documents. The evidence and consensus opinion consistently favoured an organized, centralized system with multidisciplinary team membership as the optimal approach for the delivery of diagnostic cancer assessment services. Independent external stakeholders agreed (with higher mean values, maximum 5, indicating stronger agreement) that DAP standards are needed (mean: 4.6), that standards should be formally approved (mean: 4.3), and importantly, that standards reflect an effective approach that will lead to quality improvements in the cancer system (mean: 4.5) and in patient care (mean: 4.3). INTERPRETATION: Based on the best available evidence, standards for the organization of DAPS are offered. There is clear need to integrate formal and comprehensive evaluation strategies with the implementation of the standards to advance this field.

Epilepsy in children with infantile thiamine deficiency.

OBJECTIVE: To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula. METHODS: The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described. RESULTS: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction. CONCLUSIONS: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

A coordinated school health approach to obesity prevention among Appalachian youth: the Winning with Wellness Pilot Project.

Childhood obesity has been an increasing problem in the United States, especially in rural areas. Effective prevention approaches are needed. This article describes the development, implementation, effectiveness, feasibility, and sustainability of a school-based obesity prevention pilot project, Winning with Wellness. The program was based on the coordinated school health model and included a community-based participatory research approach aimed at promoting healthy eating and physical activity in a rural Appalachian elementary school. Findings from this preliminary project revealed improvements in nutrition offerings and increased physical activity during the school day. In addition, the program was found to be acceptable to teachers, successfully implemented utilizing both existing and newly developed resources, and sustainable as evidenced in continued practice and expansion to other area schools.

Multicenter long-term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin.

BACKGROUND AND PURPOSE: Long-term follow-up of children with idiopathic West syndrome (WS) treated with adrenocorticotropic hormone (ACTH) or vigabatrin. METHODS: Records of 28 normal magnetic resonance imaging (MRI) WS cases were reviewed for seizure development and cognitive outcome in relation to treatment type and lag. RESULTS: Average age at disease onset was 5.5 months, and average lag time to treatment was 25 days. Fourteen patients were treated with ACTH (eight early and six late), and 14 with vigabatrin (without delay). Response rates were 88% for ACTH and 80% for vigabatrin. Short-term outcomes for seizure cessation and electroencephalography normalization were identical between the groups. In the long-term, early ACTH treatment was better than the rest combined. Average follow-up time was 9 years. A normal cognitive outcome was achieved in 100% of the early-ACTH group, 67% of the late-ACTH group and 54% of the vigabatrin group (P = 0.03). Seizures subsequently developed in 54% of the vigabatrin group, in 33% of the late ACTH group, and 0% of the early ACTH group (P < 0.05). CONCLUSIONS: Idiopathic WS with normal MRI is associated with a good cognitive outcome. Early ACTH treatment, administered within 1 month, yields a better cognitive and seizure outcome than vigabatrin or late ACTH.