In†Situ Synthesis of an Aptamer-Based Polyvalent Antibody Mimic on the Cell Surface for Enhanced Interactions between Immune and Cancer Cells.

An ability to promote therapeutic immune cells to recognize cancer cells is important for the success of cell-based cancer immunotherapy. We present a synthetic method for functionalizing the surface of natural killer (NK) cells with a supramolecular aptamer-based polyvalent antibody mimic (PAM). The PAM is synthesized on the cell surface through nucleic acid assembly and hybridization. The data show that PAM has superiority over its monovalent counterpart in powering NKs to bind to cancer cells, and that PAM-engineered NK cells exhibit the capability of killing cancer cells more effectively. Notably, aptamers can, in principle, be discovered against any cell receptors; moreover, the aptamers can be replaced by any other ligands when developing a PAM. Thus, this work has successfully demonstrated a technology platform for promoting interactions between immune and cancer cells.

Dyadic psychological intervention for patients with cancer and caregivers in home-based specialized palliative care: The Domus model.

ABSTRACTObjective:Patients with incurable cancer and their informal caregivers have numerous psychological and psychosocial needs. Many of these patients wish to receive their care and die at home. Few home-based specialized palliative care (SPC) interventions systematically integrate psychological support. We present a psychological intervention for patient-caregiver dyads developed for an ongoing randomized controlled trial (RCT) of home-based SPC, known as Domus, as well as the results of an assessment of its acceptability and feasibility. METHOD: The Domus model of SPC for patients with incurable cancer and their caregivers offered systematic psychological assessment and dyadic intervention as part of interdisciplinary care. Through accelerated transition to SPC, the aim of the model was to enhance patients' chances of receiving care and dying at home. Integration of psychological support sought to facilitate this goal by alleviating distress in patients and caregivers. Psychologists provided needs-based sessions based on existential-phenomenological therapy. Feasibility and acceptability were investigated by examining enrollment, nonparticipation, and completion of psychological sessions. RESULTS: Enrollment in the RCT and uptake of the psychological intervention indicated that it was feasible and acceptable to patients and caregivers. The strengths of the intervention included its focus on dyads, psychological distress, and existential concerns, as well as interdisciplinary collaboration and psychological interventions offered according to need. Its main limitation was a lack of an intervention for other family members. SIGNIFICANCE OF RESULTS: Our results show that psychological intervention can be systematically integrated into SPC and that it appears feasible to provide dyadic needs-based sessions with an existential therapeutic approach. The Domus RCT will provide evidence of the efficacy of a novel model of multidisciplinary SPC.

Polyvalent Display of Biomolecules on Live Cells.

Surface display of biomolecules on live cells offers new opportunities to treat human diseases and perform basic studies. Existing methods are primarily focused on monovalent functionalization, that is, the display of single biomolecules across the cell surface. Here we show that the surface of live cells can be functionalized to display polyvalent biomolecular structures through two-step reactions under physiological conditions. This polyvalent functionalization enables the cell surface to recognize the microenvironment one order of magnitude more effectively than with monovalent functionalization. Thus, polyvalent display of biomolecules on live cells holds great potential for various biological and biomedical applications.

A critical reanalysis of the relationship between genomics and well-being.

Fredrickson et al. [Fredrickson BL, et al. (2013) Proc Natl Acad Sci USA 110(33):13684-13689] claimed to have observed significant differences in gene expression related to hedonic and eudaimonic dimensions of well-being. Having closely examined both their claims and their data, we draw substantially different conclusions. After identifying some important conceptual and methodological flaws in their argument, we report the results of a series of reanalyses of their dataset. We first applied a variety of exploratory and confirmatory factor analysis techniques to their self-reported well-being data. A number of plausible factor solutions emerged, but none of these corresponded to Fredrickson et al.'s claimed hedonic and eudaimonic dimensions. We next examined the regression analyses that purportedly yielded distinct differential profiles of gene expression associated with the two well-being dimensions. Using the best-fitting two-factor solution that we identified, we obtained effects almost twice as large as those found by Fredrickson et al. using their questionable hedonic and eudaimonic factors. Next, we conducted regression analyses for all possible two-factor solutions of the psychometric data; we found that 69.2% of these gave statistically significant results for both factors, whereas only 0.25% would be expected to do so if the regression process was really able to identify independent differential gene expression effects. Finally, we replaced Fredrickson et al.'s psychometric data with random numbers and continued to find very large numbers of apparently statistically significant effects. We conclude that Fredrickson et al.'s widely publicized claims about the effects of different dimensions of well-being on health-related gene expression are merely artifacts of dubious analyses and erroneous methodology.

Exploring synergistic interactions and catalysts in complex interventions: longitudinal, mixed methods case studies of an optimised multi-level suicide prevention intervention in four european countries (Ospi-Europe).

BACKGROUND: The Medical Research Council (MRC) Framework for complex interventions highlights the need to explore interactions between components of complex interventions, but this has not yet been fully explored within complex, non-pharmacological interventions. This paper draws on the process evaluation data of a suicide prevention programme implemented in four European countries to illustrate the synergistic interactions between intervention levels in a complex programme, and to present our method for exploring these. METHODS: A realist evaluation approach informed the process evaluation, which drew on mixed methods, longitudinal case studies. Data collection consisted of 47 semi-structured interviews, 12 focus groups, one workshop, fieldnoted observations of six programme meetings and 20 questionnaires (delivered at six month intervals to each of the four intervention sites). Analysis drew on the framework approach, facilitated by the use of QSR NVivo (v10). Our qualitative approach to exploring synergistic interactions (QuaSIC) also developed a matrix of hypothesised synergies that were explored within one workshop and two waves of data collection. RESULTS: All four implementation countries provided examples of synergistic interactions that added value beyond the sum of individual intervention levels or components in isolation. For instance, the launch ceremony of the public health campaign (a level 3 intervention) in Ireland had an impact on the community-based professional training, increasing uptake and visibility of training for journalists in particular. In turn, this led to increased media reporting of OSPI activities (monitored as part of the public health campaign) and also led to wider dissemination of editorial guidelines for responsible reporting of suicidal acts. Analysis of the total process evaluation dataset also revealed the new phenomenon of the OSPI programme acting as a catalyst for externally generated (and funded) activity that shared the goals of suicide prevention. CONCLUSIONS: The QuaSIC approach enabled us to develop and refine our definition of synergistic interactions and add the innovative concept of catalytic effects. This represents a novel approach to the evaluation of complex interventions. By exploring synergies and catalytic interactions related to a complex intervention or programme, we reveal the added value to planned activities and how they might be maximised.

Role of patient treatment beliefs and provider characteristics in establishing patient-provider relationships.

BACKGROUND: Positive patient-provider relationships have been associated with improved depression treatment outcomes. Little is known about how patient treatment beliefs influence patient-provider relationships, specifically treatment alliance and shared decision making in primary care (PC). OBJECTIVE: We evaluated the relationship between patient treatment beliefs and patient-provider relationships by gender, race and current depression. METHODS: We used a deductive parallel convergent mixed method design with cross-sectional data. Participants were 227 Black and White patients presenting with depression symptoms in PC settings. Individuals were randomized into either a quantitative survey (n = 198) or qualitative interview (n = 29) group. We used multiple ordinary least squares regression to evaluate the association between patient beliefs, as measured by the Treatment Beliefs Scale and the Medication Beliefs Scale, and treatment alliance or shared decision making. We concurrently conducted thematic analyses of qualitative semistructured interview data to explicate the nature of patient-provider relationships. RESULTS: We found that patients who believed their provider would respectfully facilitate depression treatment reported greater bond, openness and shared decision making with their provider. We also identified qualitative themes of physicians listening to, caring about and respecting patients. Empathy and emotive expression increased patient trust in PC providers as facilitators of depression treatment. CONCLUSIONS: This work systematically demonstrated what many providers anecdotally believe: PC environments in which individuals feel safe sharing psychological distress are essential to early identification and treatment of depression. Interprofessional skills-based training in attentiveness and active listening may influence the effectiveness of depression intervention.

Evaluation of an implementation model: a national investigation of VA residential programs.

This national investigation utilizes qualitative data to evaluate an implementation model regarding factors influencing provider use of two evidence-based treatments for posttraumatic stress disorder (PTSD). Semi-structured qualitative interviews with 198 mental health providers from 38 Department of Veterans Affairs' (VA) residential treatment programs were used to explore these issues regarding prolonged exposure (PE) and cognitive processing therapy (CPT) in VA residential PTSD programs. Several unique and some overlapping predictors emerged. Leadership was viewed as an influence on implementation for both CPT and PE, while a lack of dedicated time and resources was viewed as a deterrent for both. Compatibility of CPT with providers' existing practices and beliefs, the ability to observe noticeable patient improvement, a perceived relative advantage of CPT over alternative treatments, and the presence of a supportive peer network emerged as influential on CPT implementation. Leadership was associated with PE implementation. Implications for the design and improvement of training and implementation efforts are discussed.

A Quantitative Test of an Implementation Framework in 38 VA Residential PTSD Programs.

This study examines the implementation of two evidence-based psychotherapies, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT), in the Department of Veterans Affairs residential Posttraumatic Stress Disorder treatment programs. Two hundred and one providers from 38 programs completed an online survey concerning implementation of PE delivered on an individual basis and CPT delivered in individual and group formats. For PE, a supportive organizational context (dedicated time and resources, and incentives and mandates) and overall positive view of the treatment were related to its implementation. For both group and individual CPT, only the supportive organizational context was significantly associated with outcome. Implications for implementation efforts are discussed.

Is implementing screening for distress an efficient means to recruit patients to a psychological intervention trial?

OBJECTIVES: Psychological interventions show greater efficacy when evaluated with distressed patients. We report on the feasibility of implementing screening for recruiting distressed cancer patients to a randomized controlled trial of problem-solving therapy (PST), characteristics associated with enrolment, and time investment and challenges of implementing screening. METHODS: Three medical settings implemented screening of patients, directly after cancer treatment (T1) and 2 months later (T2), using Hopkins Symptom Checklist-25 and one question about need for services. Distressed patients indicating need for services were interviewed. Eligible patients were offered the possibility to participate in the trial. Consenting patients were randomized to PST or waitlist. RESULTS: At T1, 366 of 970 screened patients (37%) scored above the cutoff and at T2, 208 of 689 screened patients (30%). At either or both T1 and T2, 423 patients reported distress, of whom 215 indicated need for services. Only 36 (4% of 970) patients consented to trial participation. Twenty-seven patients needed to be screened to recruit a single patient, with 17 h required for each patient recruited. Barriers to screening were time constraints and negative attitudes of oncology staff towards screening. CONCLUSIONS: Implementing screening proved inefficient for recruiting distressed cancer patients post-treatment to a randomized controlled trial on PST, with need for services being much less than anticipated. Consecutively screening patients did not result in a sample representative of the larger pool of distressed patients, which may lower generalizability. An adequately powered intervention trial using screening requires a feasibility study establishing recruitment rates and dedicated, funded staff assistance.

Triple P-Positive Parenting programs: the folly of basing social policy on underpowered flawed studies.

Wilson et al. provided a valuable systematic and meta-analytic review of the Triple P-Positive Parenting program in which they identified substantial problems in the quality of available evidence. Their review largely escaped unscathed after Sanders et al.'s critical commentary. However, both of these sources overlook the most serious problem with the Triple P literature, namely, the over-reliance on positive but substantially underpowered trials. Such trials are particularly susceptible to risks of bias and investigator manipulation of apparent results. We offer a justification for the criterion of no fewer than 35 participants in either the intervention or control group. Applying this criterion, 19 of the 23 trials identified by Wilson et al. were eliminated. A number of these trials were so small that it would be statistically improbable that they would detect an effect even if it were present. We argued that clinicians and policymakers implementing Triple P programs incorporate evaluations to ensure that goals are being met and resources are not being squandered.Please see related articles http://www.biomedcentral.com/1741-7015/10/130 and http://www.biomedcentral.com/1741-7015/10/145.

Developing social capital in implementing a complex intervention: a process evaluation of the early implementation of a suicide prevention intervention in four European countries.

BACKGROUND: Variation in the implementation of complex multilevel interventions can impact on their delivery and outcomes. Few suicide prevention interventions, especially multilevel interventions, have included evaluation of both the process of implementation as well as outcomes. Such evaluation is essential for the replication of interventions, for interpreting and understanding outcomes, and for improving implementation science. This paper reports on a process evaluation of the early implementation stage of an optimised suicide prevention programme (OSPI-Europe) implemented in four European countries. METHODS: The process analysis was conducted within the framework of a realist evaluation methodology, and involved case studies of the process of implementation in four European countries. Datasets include: repeated questionnaires to track progress of implementation including delivery of individual activities and their intensity; serial interviews and focus groups with stakeholder groups; and detailed observations at OSPI implementation team meetings. RESULTS: Analysis of local contexts in each of the four countries revealed that the advisory group was a key mechanism that had a substantial impact on the ease of implementation of OSPI interventions, particularly on their ability to recruit to training interventions. However, simply recruiting representatives of key organisations into an advisory group is not sufficient to achieve impact on the delivery of interventions. In order to maximise the potential of high level 'gatekeepers', it is necessary to first transform them into OSPI stakeholders. Motivations for OSPI participation as a stakeholder included: personal affinity with the shared goals and target groups within OSPI; the complementary and participatory nature of OSPI that adds value to pre-existing suicide prevention initiatives; and reciprocal reward for participants through access to the extended network capacity that organisations could accrue for themselves and their organisations from participation in OSPI. CONCLUSIONS: Exploring the role of advisory groups and the meaning of participation for these participants revealed some key areas for best practice in implementation: careful planning of the composition of the advisory group to access target groups; the importance of establishing common goals; the importance of acknowledging and complementing existing experience and activity; and facilitating an equivalence of benefit from network participation.

Is screening effective in detecting untreated psychiatric disorders among newly diagnosed breast cancer patients?

BACKGROUND: A key purpose of routine distress screening is to ensure that cancer patients receive appropriate mental health care. Most studies validating screening instruments overestimate the effectiveness of screening by not differentiating between patients with untreated disorders and patients who are already being treated. This study adopts the novel strategy of evaluating the effectiveness of screening after correcting for disorder for which treatment is already being provided. METHODS: A total of 437 recently diagnosed breast cancer patients received in-clinic distress screening and telephone-based psychiatric interviews. Analyses were conducted using receipt of psychotropic medication for mental health difficulties in the context of a psychiatric disorder as a proxy for identification and treatment. RESULTS: Rates of elevated distress (33%), major depressive disorder (8%), minor depression (6%), dysthymia (2%), or generalized anxiety disorder (3%) were similar to those in other samples. Thirty-six percent of patients received psychotropic medication around the time of cancer diagnosis, including 64% of those with a current psychiatric diagnosis. Although 39% of patients with elevated distress had a psychiatric disorder, the positive predictive value of screening fell to 15% for an untreated psychiatric disorder and 6% had untreated depression. CONCLUSION: Given the high rates of existing treatment, screening may not be efficient for identifying untreated disorder. Almost two-thirds of patients with treated disorders remain symptomatic. Use of symptom scales might reasonably be expanded to surveillance of treatment response or ruling out disorder. Substantial resources would likely be required to coordinate or manage psychiatric care among patients, as would a willingness to intervene in existing relationships with other providers.

Lack of prognostic value of type D personality for mortality in a large sample of heart failure patients.

BACKGROUND: Type D personality has been proposed as a prognostic indicator for mortality in cardiovascular disease. Most research examining this construct originates from one research group, and it is critical that the predictive value of Type D personality for adverse outcomes is independently cross-validated. This study examined its prognostic value in heart failure, relative to B-type natriuretic peptide (BNP) and depressive symptoms. METHODS: We studied 706 patients with complete BNP, depressive symptom, and Type D personality and mortality data from 958 patients with heart failure enrolled after hospitalization for a multisite study of a disease management program. Multivariable models were adjusted for BNP and depression. RESULTS: At 18 months, there were 192 deaths (27.2%). No evidence was found for a prognostic value of Type D personality in the unadjusted model (hazard ratio [HR] = 0.893, 95% confidence interval [CI] = 0.582-1.370). In contrast, BNP was significantly predictive of mortality (HR = 1.588, 95% CI = 1.391-1.812), whereas depression was not (HR = 1.011, 95% CI = 0.998-1.024). Type D was also not predictive in covariate-adjusted models (HR = 0.779, 95% CI = 0.489-1.242). Similar results were obtained when analyzing Type D as the interaction between continuous z scores of its two components, negative affectivity and social inhibition (p = .144). CONCLUSIONS: In the largest study to date, Type D does not predict mortality. Future research should construe Type D as the interaction of continuous negative affectivity and social inhibition z scores, rather than as a typology, and consider analyses replacing negative affectivity with depression.

Cultural, economic, and psychological predictors of colonoscopy in a national sample.

BACKGROUND: Although colorectal cancer (CRC) is the second leading cause of cancer death among adults in the US and colonoscopy is efficacious in reducing morbidity and mortality from CRC, screening rates are sub-optimal. Understanding the socioeconomic, cultural, and health care context within which decisions about colonoscopy are made allows physicians to address patients' most salient beliefs and values and other constraints when making screening recommendations. OBJECTIVE: To evaluate the direct and interactive effects of socioeconomics, health care variables, psychological characteristics, and cultural values on colonoscopy use. DESIGN, SETTING, PARTICIPANTS: National survey completed between January-August 2009 in a random sample of African American, white, and Hispanic adults ages 50-75 without cancer (n = 582). MAIN MEASURE: Self-reported colonoscopy use. KEY RESULTS: Only 59% of respondents reported having a colonoscopy. The likelihood of colonoscopy increased with having health insurance (OR = 2.82, 95% CI = 1.24, 6.43, p = 0.004), and increasing age (OR = 1.40, 95% CI = 1.11, 1.77, p = 0.001). In addition, respondents with greater self-efficacy were more likely to have a colonoscopy (OR = 2.41, 95% CI = 1.35, 4.29, p = 0.003). CONCLUSIONS: Programs that help patients to overcome access and psychological barriers to screening are needed.

Does screening for distress efficiently uncover meetable unmet needs in cancer patients?

OBJECTIVES: We evaluated screening for distress in terms of its ability to uncover unmet need for psychosocial services in cancer patients. Correlates of distress, need for services and met and unmet need for services were investigated. METHODS: Immediately after cancer treatment (T1) and 2 months later (T2), 302 patients completed the Hopkins Symptom Checklist-25 (HSCL-25) and a single question assessing the need for services. All distressed patients (HSCL-25≥39) and non-distressed patients endorsing a need for services were then called (n = 99) to assess their need. RESULTS: Thirty-seven percent (T1) and 31% (T2) of patients were distressed and 31% (T1) and 18% (T2) expressed the need for services. Both time points showed higher distress in younger patients and females and lower distress in prostate cancer and patients treated by radiotherapy only. Less need for services was found in prostate cancer (T1), greater need was related to being single (T1) and younger (T2). Distress and need for services were positively related (p<0.001). The HSCL-25 showed modest sensitivity (T1: 0.59, T2: 0.65) and specificity (T1: 0.75, T2: 0.78) as an indicator of need for services. Interviews at T2 revealed that 51% of distressed patients needed no psychosocial services and 25% were already receiving services. At T2, regardless of distress level, 10% of all screened patients reported an unmet need for psychosocial services. CONCLUSIONS: Depending on the clinical context, screening might be more efficient if it assessed the unmet need for services rather than distress. More attention should be concentrated on directing patients with meetable unmet needs to available services.

Are treatment preferences relevant in response to serotonergic antidepressants and cognitive-behavioral therapy in depressed primary care patients? Results from a randomized controlled trial including a patients' choice arm.

BACKGROUND: Little is known about the influence of depressed patients' preferences and expectations about treatments upon treatment outcome. We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment. METHODS: Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline; placebo; cognitive-behavioral group therapy, CBT-G; moderated self-help group control; treatment with sertraline or CBT-G according to patients' choice), outcomes for 145 primary care patients with mild-to-moderate depressive disorders according to DSM-IV criteria were investigated. Preference for medication versus psychotherapy was assessed at screening using a single item. Post-baseline difference scores for the Hamilton Depression Rating Scale (HAMD-17) were used to assess treatment outcome (mixed-model repeated-measures regression analysis). RESULTS: Depressed patients receiving their preferred treatment (n = 63), whether sertraline or CBT-G, responded significantly better than those who did not receive their preferred therapy (n = 54; p = 0.001). The difference in outcome between both groups was 8.0 points on the HAMD-17 for psychotherapy and 2.9 points on the HAMD-17 for treatment with antidepressants. Results were not explained by differences in depression severity or dropout rates. CONCLUSIONS: Patients' relative preference for medication versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: +2.9 points for drugs; +8.0 points for CBT-G) in outcome.

Detection of depression in older adults by family and friends: distinguishing mood disorder signals from the noise of personality and everyday life.

BACKGROUND: The capacity of friends and family member informants to make judgments about the presence of a mood disorder history in an older primary care patient has theoretical, clinical, and public health significance. This study examined the accuracy of informant-reported mood disorder diagnoses in a sample of primary care patients aged 65 years or older. We hypothesized that the accuracy (sensitivity and specificity) of informant reports would vary with the patient's personality. METHODS: Hypotheses were tested in 191 dyads consisting of patients and their friends or relatives (informants) recruited from primary care settings. Gold-standard mood disorder diagnoses were established at consensus conferences based on a review of medical charts and data collected in a structured interview with the patient. Patients completed an assessment battery that included the NEO-Five Factor Inventory. RESULTS: Sensitivity and specificity of informant-derived mood disorder diagnoses were related to patient personality. Sensitivity of informant-derived lifetime mood disorder diagnoses was compromised by higher Extraversion and higher Agreeableness. Specificity of informant-derived lifetime mood disorder diagnoses was compromised by lower Agreeableness and higher Conscientiousness. CONCLUSION: Patient personality has implications for the accuracy of mood disorder histories provided by friends and family members. Given that false negatives can have grave consequences, we recommend that practitioners be particularly vigilant when interpreting collateral information about their extraverted, agreeable patients.

Reporting of conflicts of interest in meta-analyses of trials of pharmacological treatments.

CONTEXT: Disclosure of conflicts of interest (COIs) from pharmaceutical industry study funding and author-industry financial relationships is sometimes recommended for randomized controlled trials (RCTs) published in biomedical journals. Authors of meta-analyses, however, are not required to report COIs disclosed in original reports of included RCTs. OBJECTIVE: To investigate whether meta-analyses of pharmacological treatments published in high-impact biomedical journals report COIs disclosed in included RCTs. DATA SOURCES AND STUDY SELECTION: We selected the 3 most recent meta-analyses of patented pharmacological treatments published January 2009 through October 2009 in each general medicine journal with an impact factor of at least 10; in high-impact journals in each of the 5 specialty medicine areas with the greatest 2008 global therapeutic sales (oncology, cardiology, respiratory medicine, endocrinology, and gastroenterology); and in the Cochrane Database of Systematic Reviews. DATA EXTRACTION: Two investigators independently extracted data on disclosed study funding, author-industry financial ties, and author employment from each meta-analysis, from RCTs included in each meta-analysis, and on whether meta-analyses reported disclosed COIs of included RCTs. RESULTS: Of 29 meta-analyses reviewed, which included 509 RCTs, only 2 meta-analyses (7%) reported RCT funding sources; and 0 reported RCT author-industry ties or employment by the pharmaceutical industry. Of 318 meta-analyzed RCTs that reported funding sources, 219 (69%) were industry funded; and 91 of 132 (69%) that reported author financial disclosures had 1 or more authors with pharmaceutical industry financial ties. In 7 of the 29 meta-analyses reviewed, 100% of included RCTs had at least 1 form of disclosed COI (pharmaceutical industry funding, author-industry financial ties, or employment), yet only 1 of these 7 meta-analyses reported RCT funding sources, and 0 reported RCT author-industry ties or employment. CONCLUSION: Among a group of meta-analyses of pharmacological treatments published in high-impact biomedical journals, information concerning primary study funding and author COIs for the included RCTs were only rarely reported.