Systematic reviews published in higher impact clinical journals were of higher quality.

OBJECTIVES To compare the methodological quality of systematic reviews (SRs) published in high- and low-impact factor (IF) Core Clinical Journals. In addition, we aimed to record the implementation of aspects of reporting, including Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram, reasons for study exclusion, and use of recommendations for interventions such as Grading of Recommendations Assessment, Development and Evaluation (GRADE). STUDY DESIGN AND SETTING We searched PubMed for systematic reviews published in Core Clinical Journals between July 1 and December 31, 2012. We evaluated the methodological quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. RESULTS Over the 6-month period, 327 interventional systematic reviews were identified with a mean AMSTAR score of 63.3% (standard deviation, 17.1%), when converted to a percentage scale. We identified deficiencies in relation to a number of quality criteria including delineation of excluded studies and assessment of publication bias. We found that SRs published in higher impact journals were undertaken more rigorously with higher percentage AMSTAR scores (per IF unit: β = 0.68%; 95% confidence interval: 0.32, 1.04; P < 0.001), a discrepancy likely to be particularly relevant when differences in IF are large. CONCLUSION Methodological quality of SRs appears to be better in higher impact journals. The overall quality of SRs published in many Core Clinical Journals remains suboptimal.

Allgemeiner Zugang zu Polyaminen mit Ethan-1,2-diamin-Einheiten: Synthese von nicht natürlich vorkommenden homologen und isomerenN1,4-Di(4-cumaroyl)sperminen

The synthesis of the three N,N′-di(4-coumaroyl)tetramines, i.e., of (E,E)-N-{3-[(2-aminoethyl)amino]propyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1a), (E,E)-N-{4-[(2-aminoethyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1b), and (E,E)-N-{6-[(2-aminoethyl)amino]hexyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1c), is described. It proceeds through stepwise construction of the symmetric polyamine backbone including protection and deprotection steps of the amino functions. Their behavior on TLC in comparison with that of 1,4-di(4-coumaroyl)spermine (=(E,E)-N-{4-[(3-aminopropyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(propane-1,3-diyl)bis[prop-2-enamide]; 2) is discussed.

Synthesis and incorporation into a-DNA of a novel conformationally constrained alpha-nucleoside analogue

We describe the synthesis and incorporation into alpha-DNA of a novel conformationally constrained alpha-nucleoside analogue. The carbohydrate part of this analogue was prepared in 4 steps from the known bicyclic precursor 1 via a stereospecific, intramolecular, Et 3B mediated radical addition to a keto-function as the key step. The thus obtained intermediate 4 was transformed stereoselectively into the corresponding alpha-nucleoside analogues 7 and 8 containing the bases adenine and thymine, and were further elaborated into the phosphoramidite building blocks 11 and 12 . Both building blocks were incorporated into alpha-oligodeoxynucleotides and their pairing behavior to parallel complementary DNA studied by UV-melting experiments. Single substitutions of alpha-deoxyribnucleoside units by the new analogues in the center of duplexes were found to be thermally destabilizing by only -0.8 to -3.1›C.

Diagnosis and workup of 522 consecutive patients with neuroendocrine neoplasms in Switzerland.

BACKGROUND Neuroendocrine neoplasms (NENs) are difficult to diagnose. We used SwissNET data to characterise NEN patients followed in the two academic centres of western Switzerland (WS), and to compare them with patients followed in eastern Switzerland (ES) as well as with international guidelines. METHOD SwissNET is a prospective database covering data from 522 consecutive patients (285 men, 237 women) from WS (n = 99) and ES (n = 423). RESULTS Mean ± SD age at diagnosis was 59.0 ± 15.7 years. Overall, 76/522 experienced a functional syndrome, with a median interval of 1.0 (IQR: 1.0-3.0) year between symptoms onset and diagnosis. A total of 51/522 of these tumours were incidental. The primary tumour site was the small intestine (29%), pancreas (21%), appendix (18%) and lung (11%) in both regions combined. In all, 513 functional imaging studies were obtained (139 in WS, 374 in ES). Of these, 381 were 111In-pentetreotide scintigraphies and 20 were 68Ga-DOTATOC PET. First line therapy was surgery in 87% of patients, medical therapy (biotherapy or chemotherapy) in 9% and irradiation in 3% for both regions together. CONCLUSION Swiss NEN patients appear similar to what has been described in the literature. Imaging by somatostatin receptor scintigraphy (SRS) is widely used in both regions of Switzerland. In good accordance with published guidelines, data on first line therapy demonstrate the crucial role of surgery. The low incidence of biotherapy suggests that long-acting somatostatin analogues are not yet widely used for their anti-proliferative effects. The SwissNET initiative should help improve compliance with ENETS guidelines in the workup and care of NEN patients.

High tumor budding stratifies breast cancer with metastatic properties.

Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (p ≤ 0.03) and lymphatic invasion (p ≤ 0.015). In CB high tumor budding was significantly (p = 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.

Time relevance, citation of reporting guidelines, and breadth of literature search in systematic reviews in orthodontics

INTRODUCTION As the importance of systematic review (SR) conclusions relies upon the scientific rigor of methods and the currency of evidence, we aimed to investigate the currency of orthodontic SRs using as proxy the time from the initial search to publication. Additionally, SR information regarding reporting guidelines, registration, and literature searches were recorded when available. MATERIALS AND METHODS A systematic PubMed search was carried out using the Clinical Queries page to identify orthodontic SRs cited between 1 January 2008 and 7 November 2013. Data related to reporting guidelines, review registration, dates of review processing, literature search, and abstract reporting were retrieved and classified by journal type. Survival analysis was used to assess the time to reach predefined manuscript stages for orthodontic and non-orthodontic journals. RESULTS One hundred twenty seven of the originally identified 585 SRs were considered eligible. The median interval from search until publication was 13.2 months (interquartile range: IQR = 9.7 months) irrespective of the journal type. There was evidence (P = 0.05) that SRs published by non-orthodontic journals appeared in PubMed faster than in orthodontic journals (non-orthodontic: median = 6.5 months; IQR = 5.7 months; orthodontic: median = 10.2 months; IQR = 5.6 months) from submission to publication and from acceptance to publication (non-orthodontic: median = 1.5 months; IQR = 2.4 months; orthodontic: median = 6.0 months; IQR = 6.2 months; P < 0.001). More than half of these SRs did not cite adherence to any reporting guidelines, whereas all but five studies were not prospectively registered. Search of unpublished research was undertaken in approximately 21 per cent and 29 per cent of the SRs published in non-orthodontic and orthodontic periodicals, respectively. CONCLUSIONS This study indicates that SR users should be aware that median time for orthodontic SRs from search to publication is 13.2 months. SRs published in non-orthodontic journals are likely to be more current in terms of submission until time to publication and acceptance until time to publication compared with those published in orthodontic journals.

Evidence for cooler European summers during periods of changing meltwater flux to the North Atlantic

We analyzed fossil chironomids (nonbiting midges) and pollen in two lake-sediment records to reconstruct and quantify Holocene summer-temperature fluctuations in the European Alps. Chironomid and pollen records indicate five centennial-scale cooling episodes during the early- and mid-Holocene. The strongest temperature declines of ≈1°C are inferred at ≈10,700–10,500 and 8,200–7,600 calibrated 14C years B.P., whereas other temperature fluctuations are of smaller amplitude. Two forcing mechanisms have been presented recently to explain centennial-scale climate variability in Europe during the early- and mid-Holocene, both involving changes in Atlantic thermohaline circulation. In the first mechanism, changes in meltwater flux from the North American continent to the North Atlantic are responsible for changes in the Atlantic thermohaline circulation, thereby affecting circum-Atlantic climate. In the second mechanism, solar variability is the cause of Holocene climatic fluctuations, possibly triggering changes in Atlantic thermohaline overturning. Within their dating uncertainty, the two major cooling periods in the European Alps are coeval with substantial changes in the routing of North American freshwater runoff to the North Atlantic, whereas quantitatively, our climatic reconstructions show a poor agreement with available records of past solar activity. Thus, our results suggest that, during the early- and mid-Holocene, freshwater-induced Atlantic circulation changes had stronger influence on Alpine summer temperatures than solar variability and that Holocene thermohaline circulation reductions have led to summer-temperature declines of up to 1°C in central Europe.

Synchronous Holocene climatic oscillations recorded on the Swiss Plateau and at timberline in the Alps

Eight synchronous pre-Roman cold phases were found at 9600–9200, 8600–8150, 7550–6900, 6600– 6200, 5350–4900, 4600–4400, 3500–3200 and 2600–2350 radiocarbon years BP by reconstructing past climate at two sites on the Swiss Plateau and at timberline in the Alps. The cooling events during the early-and mid-Holocene represent temperature values similar to today, and apparently the onset of cooling events represents a deviation from today's mean annual temperature of about 1°C and is triggered at a 1000-year periodicity. At Wallisellen-Langachermoos (440 m), a former oligotrophic lake near Zürich, the correlation between sum mertime lake levels and the seed production of the amphi-Atlantic aquatic plantNajas flexilis was used to reconstruct lake levels over a 3000-year period during the first part of the Holocene. At Lake Seedorf on the western Swiss Plateau (609 m) the sedimentological, palynological and macrofossil record revealed fluctuations of lake levels for the complete Holocene. From Lago Basso in the southern Alps (2250 m, Val San Giacomo near Splügen Pass, Northern Italy) the terrestrial plant macrofossils – especiallyPinus cembra andLarix – allowed the reconstruction of timberline fluctuations controlled by climate. A similar climatic pattern was found at Gouillé Rion pond in the central Swiss Alps (2343 m, Val d'Hérémence) with plant macrofossils and pollen concentrations and percentages. We postulate that these climatic events are detectable throughout central Europe by independent methods in combination with precise AMS-radiocarbon datings on terrestrial plant remains. Our data fit other proxy records of regional climatic change, such as cool intervals from Greenland ice cores, glacier movements in the Swiss and Austrian Alps, and dendro-densitometry on subfossil wood, as well as the palaeoclimatic data from the Jura Mountains of France obtained by sedimentological analyses. Thus our data indicate that the Northern Hemisphere climate was less stable during the Holocene than previously believed.

Discrepancies in Outcome Reporting Exist Between Protocols and Published Oral Health Cochrane Systematic Reviews

OBJECTIVES To assess discrepancies in the analyzed outcomes between protocols and published reviews within Cochrane oral health systematic reviews (COHG) on the Cochrane Database of Systematic Reviews (CDSR). STUDY DESIGN AND SETTING All COHG systematic reviews on the CDSR and the corresponding protocols were retrieved in November 2014 and information on the reported outcomes was recorded. Data was collected at the systematic review level by two reviewers independently. RESULTS One hundred and fifty two reviews were included. In relation to primary outcomes, 11.2% were downgraded to secondary outcomes, 9.9% were omitted altogether in the final publication and new primary outcomes were identified in 18.4% of publications. For secondary outcomes, 2% were upgraded to primary, 12.5% were omitted and 30.9% were newly introduced in the publication. Overall, 45.4% of reviews had at least one discrepancy when compared to the protocol; these were reported in 14.5% reviews. The number of review updates appears to be associated with discrepancies between final review and protocol (OR: 3.18, 95% CI: 1.77, 5.74, p<0.001). The risk of reporting significant results was lower for both downgraded outcomes [RR: 0.52, 95% CI: 0.17, 1.58, p = 0.24] and upgraded or newly introduced outcomes [RR: 0.77, 95% CI: 0.36, 1.64, p = 0.50] compared to outcomes with no discrepancies. The risk of reporting significant results was higher for upgraded or newly introduced outcomes compared to downgraded outcomes (RR = 1.19, 95% CI: 0.65, 2.16, p = 0.57). None of the comparisons reached statistical significance. CONCLUSION While no evidence of selective outcome reporting was found in this study, based on the present analysis of SRs published within COHG systematic reviews, discrepancies between outcomes in pre-published protocols and final reviews continue to be common. Solutions such as the use of standardized outcomes to reduce the prevalence of this issue may need to be explored.

Use of quality assessment tools in systematic reviews was varied and inconsistent

OBJECTIVES To assess the use of quality assessment tools among a cross-section of systematic reviews (SRs) and to further evaluate whether quality was used as a parameter in the decision to include primary studies within subsequent meta-analysis. STUDY DESIGN AND SETTING We searched PubMed for SRs (interventional, observational, and diagnostic) published in Core Clinical Journals between January 1 and March 31, 2014. RESULTS Three hundred nine SRs were identified. Quality assessment was undertaken in 222 (71.8%) with isolated use of the Cochrane risk of bias tool (26.1%, n = 58) and the Newcastle-Ottawa Scale (15.3%, n = 34) most common. A threshold level of primary study quality for subsequent meta-analysis was used in 12.9% (40 of 309) of reviews. Overall, fifty-four combinations of quality assessment tools were identified with a similar preponderance of tools used among observational and interventional reviews. Multiple tools were used in 11.7% (n = 36) of SRs overall. CONCLUSION We found that quality assessment tools were used in a majority of SRs; however, a threshold level of quality for meta-analysis was stipulated in just 12.9% (n = 40). This cross-sectional analysis provides further evidence of the need for more active or intuitive editorial processes to enhance the reporting of SRs.

The evidence from systematic reviews and meta-analyses published in orthodontic literature. Where do we stand?

AIM To analyse meta-analyses included in systematic reviews (SRs) published in leading orthodontic journals and the Cochrane Database of Systematic Reviews (CDSR) focusing on orthodontic literature and to assess the quality of the existing evidence. MATERIALS AND METHODS Electronic searching was undertaken to identify SRs published in five major orthodontic journals and the CDSR between January 2000 and June 2014. Quality assessment of the overall body of evidence from meta-analyses was conducted using the Grading of Recommendations Assessment, Development and Evaluation working group (GRADE) tool. RESULTS One hundred and fifty-seven SRs were identified; meta-analysis was present in 43 of these (27.4 per cent). The highest proportion of SRs that included a meta-analysis was found in Orthodontics and Craniofacial Research (6/13; 46.1 per cent), followed by the CDSR (12/33; 36.4 per cent) and the American Journal of Orthodontics and Dentofacial Orthopaedics (15/44; 34.1 per cent). Class II treatment was the most commonly addressed topic within SRs in orthodontics (n = 18/157; 11.5 per cent). The number of trials combined to produce a summary estimate was small for most meta-analyses with a median of 4 (range: 2-52). Only 21 per cent (n = 9) of included meta-analyses were considered to have a high/moderate quality of evidence according to GRADE, while the majority were of low or very low quality (n = 34; 79.0 per cent). CONCLUSIONS Overall, approximately one quarter of orthodontic SRs included quantitative synthesis, with a median of four trials per meta-analysis. The overall quality of evidence from the selected orthodontic SRs was predominantly low to very low indicating the relative lack of high quality of evidence from SRs to inform clinical practice guidelines.