Why we habitually engage in null-hypothesis significance testing:A qualitative study

BACKGROUND: Null Hypothesis Significance Testing (NHST) is the most familiar statistical procedure for making inferences about population effects. Important problems associated with this method have been addressed and various alternatives that overcome these problems have been developed. Despite its many well-documented drawbacks, NHST remains the prevailing method for drawing conclusions from data. Reasons for this have been insufficiently investigated. Therefore, the aim of our study was to explore the perceived barriers and facilitators related to the use of NHST and alternative statistical procedures among relevant stakeholders in the scientific system. METHODS: Individual semi-structured interviews and focus groups were conducted with junior and senior researchers, lecturers in statistics, editors of scientific journals and program leaders of funding agencies. During the focus groups, important themes that emerged from the interviews were discussed. Data analysis was performed using the constant comparison method, allowing emerging (sub)themes to be fully explored. A theory substantiating the prevailing use of NHST was developed based on the main themes and subthemes we identified. RESULTS: Twenty-nine interviews and six focus groups were conducted. Several interrelated facilitators and barriers associated with the use of NHST and alternative statistical procedures were identified. These factors were subsumed under three main themes: the scientific climate, scientific duty, and reactivity. As a result of the factors, most participants feel dependent in their actions upon others, have become reactive, and await action and initiatives from others. This may explain why NHST is still the standard and ubiquitously used by almost everyone involved. CONCLUSION: Our findings demonstrate how perceived barriers to shift away from NHST set a high threshold for actual behavioral change and create a circle of interdependency between stakeholders. By taking small steps it should be possible to decrease the scientific community’s strong dependence on NHST and p-values

The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population

Dickkopf-3 (DKK3) is an emerging biomarker for cardiovascular disease (CVD) and chronic kidney disease (CKD). Herein, baseline DKK3 plasma levels were measured in 8420 subjects from the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort, a large general population cohort, using enzyme-linked immunosorbent assays. Associations with clinical variables and outcomes were analysed. Median DKK3 level was 32.8 ng/ml (28.0-39.0). In multivariable linear regression analysis, the strongest correlates for plasma DKK3 were age, body mass index and estimated glomerular filtration rate (eGFR). At baseline, 564 (6.7%) subjects had CVD (defined as a myocardial infarction and/or cerebrovascular accident) and 1361 (16.2%) subjects had CKD (defined as eGFR 30 mg/24 h). Of subjects with known CVD and CKD follow-up status (respectively 7828 and 5548), 669 (8.5%) developed CVD and 951 (17.1%) developed CKD (median follow-up respectively 12.5 and 10.2 years). Crude logistic regression analysis revealed that DKK3 levels were associated with prevalent CVD (Odds ratio: 2.14 [1.76-2.61] per DKK3 doubling,

Development of an Antimicrobial Peptide SAAP-148-Functionalized Supramolecular Coating on Titanium to Prevent Biomaterial-Associated Infections

Titanium implants are widely used in medicine but have a risk of biomaterial-associated infection (BAI), of which traditional antibiotic-based treatment is affected by resistance. Antimicrobial peptides (AMPs) are used to successfully kill antibiotic-resistant bacteria. Herein, a supramolecular coating for titanium implants is developed which presents the synthetic antimicrobial and antibiofilm peptide SAAP-148 via supramolecular interactions using ureido-pyrimidinone supramolecular units (UPy-SAAP-148GG). Material characterization of dropcast coatings shows the presence of UPy-SAAP-148GG at the surface. The supramolecular immobilized peptide remains antimicrobially active in dropcast polymer films and can successfully kill (antibiotic-resistant) Staphylococcus aureus, Acinetobacter baumannii, and Escherichia coli. Minor toxicity for human dermal fibroblasts is observed, with a reduced cell attachment after 24 h. Subsequently, a dipcoat coating on titanium implants is developed and tested in vivo in a subcutaneous implant infection mouse model with S. aureus administered locally on the implant before implantation to mimic contamination during surgery. The supramolecular coating containing 5 mol% of UPy-SAAP-148GG significantly prevents colonization of the implant surface as well as of the surrounding tissue, with no signs of toxicity. This shows that supramolecular AMP coatings on titanium are eminently suitable to prevent BAI.</p

Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study

Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan–Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2–3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan. METHODS AND ANALYSIS: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult pa

The Influence of Radiograph Obliquity on Böhler's and Gissane's Angles in Calcanei

In calcaneal fractures, Böhler's and Gissane's angles are considered important parameters to guide treatment strategy and provide prognostic information during follow-up visits. Therefore, lateral radiographs have to be accurate. The aim of this study was to evaluate the effect of craniocaudal and posteroanterior angular variations (i.e., simulate lower leg malposition) from the true lateral radiograph on Böhler's and Gissane's angles. In this radioanatomical study, 15 embalmed, skeletally mature, human anatomic lower limb specimens were used. Using predefined criteria, a true lateral radiograph (i.e., 0° angular variation) was obtained. Angular variations from this true lateral radiograph were made from –30° to +30° deviation in the craniocaudal and posteroanterior direction at 5° intervals. Böhler's and Gissane angles were independently assessed by 2 experienced trauma surgeons. Böhler's angle decreased with increasing caudal angular variations (maximum –4.3° deviation at –30°). With increasing of the posterior angular variations, Böhler's angle increased (maximum 5.0° deviation at +30°) from the true lateral radiograph, but all deviations were within the measurement error. The deviation of the angle of Gissane was most pronounced in the cranial direction, with the mean angle decreasing by

The WAGGS project - I. The WiFeS Atlas of Galactic Globular cluster Spectra

We present the WiFeS Atlas of Galactic Globular cluster Spectra, a library of integrated spectra of Milky Way and Local Group globular clusters. We used the WiFeS integral field spectrograph on the Australian National University 2.3 m telescope to observe the central regions of 64 Milky Way globular clusters and 22 globular clusters hosted by the Milky Way’s low-mass satellite galaxies. The spectra have wider wavelength coverage (3300–9050 Å) and higher spectral resolution (R = 6800) than existing spectral libraries of Milky Way globular clusters. By including Large and Small Magellanic Cloud star clusters, we extend the coverage of parameter space of existing libraries towards young and intermediate ages. While testing stellar population synthesis models and analysis techniques is the main aim of this library, the observations may also further our understanding of the stellar populations of Local Group globular clusters and make possible the direct comparison of extragalactic globular cluster integrated light observations with well-understood globular clusters in the Milky Way. The integrated spectra are publicly available via the project website

Two Major Medicinal Honeys Have Different Mechanisms of Bactericidal Activity

Honey is increasingly valued for its antibacterial activity, but knowledge regarding the mechanism of action is still incomplete. We assessed the bactericidal activity and mechanism of action of Revamil® source (RS) honey and manuka honey, the sources of two major medical-grade honeys. RS honey killed Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa within 2 hours, whereas manuka honey had such rapid activity only against B. subtilis. After 24 hours of incubation, both honeys killed all tested bacteria, including methicillin-resistant Staphylococcus aureus, but manuka honey retained activity up to higher dilutions than RS honey. Bee defensin-1 and H2O2 were the major factors involved in rapid bactericidal activity of RS honey. These factors were absent in manuka honey, but this honey contained 44-fold higher concentrations of methylglyoxal than RS honey. Methylglyoxal was a major bactericidal factor in manuka honey, but after neutralization of this compound manuka honey retained bactericidal activity due to several unknown factors. RS and manuka honey have highly distinct compositions of bactericidal factors, resulting in large differences in bactericidal activity

Serum Stabilities of Short Tryptophan- and Arginine-Rich Antimicrobial Peptide Analogs

Several short antimicrobial peptides that are rich in tryptophan and arginine residues were designed with a series of simple modifications such as end capping and cyclization. The two sets of hexapeptides are based on the Trp- and Arg-rich primary sequences from the "antimicrobial centre" of bovine lactoferricin as well as an antimicrobial sequence obtained through the screening of a hexapeptide combinatorial library.HPLC, mass spectrometry and antimicrobial assays were carried out to explore the consequences of the modifications on the serum stability and microbicidal activity of the peptides. The results show that C-terminal amidation increases the antimicrobial activity but that it makes little difference to its proteolytic degradation in human serum. On the other hand, N-terminal acetylation decreases the peptide activities but significantly increases their protease resistance. Peptide cyclization of the hexameric peptides was found to be highly effective for both serum stability and antimicrobial activity. However the two cyclization strategies employed have different effects, with disulfide cyclization resulting in more active peptides while backbone cyclization results in more proteolytically stable peptides. However, the benefit of backbone cyclization did not extend to longer 11-mer peptides derived from the same region of lactoferricin. Mass spectrometry data support the serum stability assay results and allowed us to determine preferred proteolysis sites in the peptides. Furthermore, isothermal titration calorimetry experiments showed that the peptides all had weak interactions with albumin, the most abundant protein in human serum.Taken together, the results provide insight into the behavior of the peptides in human serum and will therefore aid in advancing antimicrobial peptide design towards systemic applications