The development of PubMed search strategies for patient preferences for treatment outcomes.

BACKGROUND: The importance of respecting patients' preferences when making treatment decisions is increasingly recognized. Efficiently retrieving papers from the scientific literature reporting on the presence and nature of such preferences can help to achieve this goal. The objective of this study was to create a search filter for PubMed to help retrieve evidence on patient preferences for treatment outcomes. METHODS: A total of 27 journals were hand-searched for articles on patient preferences for treatment outcomes published in 2011. Selected articles served as a reference set. To develop optimal search strategies to retrieve this set, all articles in the reference set were randomly split into a development and a validation set. MeSH-terms and keywords retrieved using PubReMiner were tested individually and as combinations in PubMed and evaluated for retrieval performance (e.g. sensitivity (Se) and specificity (Sp)). RESULTS: Of 8238 articles, 22 were considered to report empirical evidence on patient preferences for specific treatment outcomes. The best search filters reached Se of 100 % [95 % CI 100-100] with Sp of 95 % [94-95 %] and Sp of 97 % [97-98 %] with 75 % Se [74-76 %]. In the validation set these queries reached values of Se of 90 % [89-91 %] with Sp 94 % [93-95 %] and Se of 80 % [79-81 %] with Sp of 97 % [96-96 %], respectively. CONCLUSIONS: Narrow and broad search queries were developed which can help in retrieving literature on patient preferences for treatment outcomes. Identifying such evidence may in turn enhance the incorporation of patient preferences in clinical decision making and health technology assessment

The development of CHAMP : a checklist for the appraisal of moderators and predictors

BACKGROUND: Personalized healthcare relies on the identification of factors explaining why individuals respond differently to the same intervention. Analyses identifying such factors, so called predictors and moderators, have their own set of assumptions and limitations which, when violated, can result in misleading claims, and incorrect actions. The aim of this study was to develop a checklist for critically appraising the results of predictor and moderator analyses by combining recommendations from published guidelines and experts in the field. METHODS: Candidate criteria for the checklist were retrieved through systematic searches of the literature. These criteria were evaluated for appropriateness using a Delphi procedure. Two Delphi rounds yielded a pilot checklist, which was tested on a set of papers included in a systematic review on reinforced home-based palliative care. The results of the pilot informed a third Delphi round, which served to finalize the checklist. RESULTS: Forty-nine appraisal criteria were identified in the literature. Feedback was obtained from fourteen experts from (bio)statistics, epidemiology and other associated fields elicited via three Delphi rounds. Additional feedback from other researchers was collected in a pilot test. The final version of our checklist included seventeen criteria, covering the design (e.g. a priori plausibility), analysis (e.g. use of interaction tests) and results (e.g. complete reporting) of moderator and predictor analysis, together with the transferability of the results (e.g. clinical importance). There are criteria both for individual papers and for bodies of evidence. CONCLUSIONS: The proposed checklist can be used for critical appraisal of reported moderator and predictor effects, as assessed in randomized or non-randomized studies using individual participant or aggregate data. This checklist is accompanied by a user's guide to facilitate implementation. Its future use across a wide variety of research domains and study types will provide insights about its usability and feasibilit

Doctors' alertness, contentedness and calmness before and after night shifts: a latent profile analysis

Background While night shifts are crucial for patient care, they threaten doctors’ well-being and performance. Knowledge of how the impact of night shifts differs for doctors is needed to attenuate the adverse effects of night shifts. This study aimed to obtain more precise insight into doctors’ feelings surrounding night shift by: identifying profiles based on doctors’ alertness, contentedness and calmness scores before and after night shifts (research question (RQ) 1); assessing how doctors’ pre- and post-shift profiles change (RQ2); and determining associations of doctors’ demographics and shift circumstances with alertness, contentedness and calmness change (RQ3). Methods Latent Profile Analysis using doctors’ pre- and post-shift self-rated alertness, contentedness and calmness scores was employed to identify pre- and post-shift profiles (RQ1). A cross-tabulation revealed pre- and post-shift profile changes (RQ2). Multiple regressions determined associations of demographics (i.e. age, sex, specialty) and night shift circumstances (i.e. hours worked pre-call, hours awake pre-call, shift duration, number of consecutive shifts, total hours of sleep) with alertness, contentedness and calmness change (RQ3). Results In total, 211 doctors participated with a mean age of 39.8 ± 10 years; 47.4% was male. The participants included consultants (46.4%) and trainees (53.6%) of the specialties surgery (64.5%) and obstetrics/gynaecology (35.5%). Three pre-shift (Indifferent, Ready, Engaged) and four post-shift profiles (Lethargic, Tired but satisfied, Excited, Mindful) were found. Most doctors changed from Ready to Tired but satisfied, with alertness reducing most. Age, specialty, sleep, shift duration and the number of consecutive shifts associated with alertness, contentedness and calmness changes. Conclusions The results provided nuanced insight into doctors’ feelings before and after night shifts. Future research may assess whether specific subgroups benefit from tailored interventions

Structured methodology review identified seven (RETREAT) criteria for selecting qualitative evidence synthesis approaches

OBJECTIVE: To compare and contrast different methods of qualitative evidence synthesis (QES) against criteria identified from the literature and to map their attributes to inform selection of the most appropriate QES method to answer research questions addressed by qualitative research. STUDY DESIGN AND SETTING: Electronic databases, citation searching and a study register were used to identify studies reporting QES methods. Attributes compiled from 26 methodological papers (2001-2014) were used as a framework for data extraction. Data were extracted into summary tables by one reviewer and then considered within the author team. RESULTS: We identified seven considerations determining choice of methods from the methodological literature, encapsulated within the mnemonic RETREAT (Review question - Epistemology - Time/Timescale - Resources - Expertise - Audience and purpose - Type of Data). We mapped 15 different published QES methods against these seven criteria. The final framework focuses on stand-alone QES methods but may also hold potential when integrating quantitative and qualitative data. CONCLUSION: These findings offer a contemporary perspective as a conceptual basis for future empirical investigation of the advantages and disadvantages of different methods of QES. It is hoped that this will inform appropriate selection of QES approaches

BCL11B Regulates Epithelial Proliferation and Asymmetric Development of the Mouse Mandibular Incisor

Mouse incisors grow continuously throughout life with enamel deposition uniquely on the outer, or labial, side of the tooth. Asymmetric enamel deposition is due to the presence of enamel-secreting ameloblasts exclusively within the labial epithelium of the incisor. We have previously shown that mice lacking the transcription factor BCL11B/CTIP2 (BCL11B hereafter) exhibit severely disrupted ameloblast formation in the developing incisor. We now report that BCL11B is a key factor controlling epithelial proliferation and overall developmental asymmetry of the mouse incisor: BCL11B is necessary for proliferation of the labial epithelium and development of the epithelial stem cell niche, which gives rise to ameloblasts; conversely, BCL11B suppresses epithelial proliferation, and development of stem cells and ameloblasts on the inner, or lingual, side of the incisor. This bidirectional action of BCL11B in the incisor epithelia appears responsible for the asymmetry of ameloblast localization in developing incisor. Underlying these spatio-specific functions of BCL11B in incisor development is the regulation of a large gene network comprised of genes encoding several members of the FGF and TGFβ superfamilies, Sprouty proteins, and Sonic hedgehog. Our data integrate BCL11B into these pathways during incisor development and reveal the molecular mechanisms that underlie phenotypes of both Bcl11b−/− and Sprouty mutant mice

Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption we performed a population based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals respectively from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2,446,724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of fifteen independent loci, with ten loci reaching genome-wide significance (p<5x10−8) for ‘age at first tooth’ and eleven loci for ‘number of teeth’. Together these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including a SNP in the protein-coding region of BMP4 (rs17563, P= 9.080x10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development

Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy.

BACKGROUND: Immunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described. METHODS: We used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells. RESULTS: Our study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth. CONCLUSIONS: Our results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy

EpCAM as multi-tumour target for near-infrared fluorescence guided surgery

Background: Evaluation of resection margins during cancer surgery can be challenging, often resulting in incomplete tumour removal. Fluorescence-guided surgery (FGS) aims to aid the surgeon to visualize tumours and resection margins during surgery. FGS relies on a clinically applicable imaging system in combination with a specific tumour-targeting contrast agent. In this study EpCAM (epithelial cell adhesion molecule) is evaluated as target for FGS in combination with the novel Artemis imaging system. Methods: The NIR fluorophore IRDye800CW was conjugated to the well-established EpCAM specific monoclonal antibody 323/A3 and an isotype IgG1 as control. The anti-EpCAM/800CW conjugate was stable in serum and showed preserved binding capacity as evaluated on EpCAM positive and negative cell lines, using flow cytometry and cell-based plate assays. Four clinically relevant orthotopic tumour models, i.e. colorectal cancer, breast cancer, head and neck cancer, and peritonitis carcinomatosa, were used to evaluate the performance of the anti-EpCAM agent with the clinically validated Artemis imaging system. The Pearl Impulse small animal imaging system was used as reference. The specificity of the NIRF signal was confirmed using bioluminescence imaging and green-fluorescent protein. Results: All tumour types could clearly be delineated and resected 72 h after injection of the imaging agent. Using NIRF imaging millimetre sized tumour nodules were detected that were invisible for the naked eye. Fluorescence microscopy demonstrated the distribution and tumour specificity of the anti-EpCAM agent. Conclusions: This study shows the potential of an EpCAM specific NIR-fluorescent agent in combination with a clinically validated intraoperative imaging system to visualize various tumours during surgery

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty

Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma

Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin avβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin avβ6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P < 0.001, respectively) and CP (P=0.003 and P < 0.001, respectively). Avβ6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, avβ6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC