Explaining Risk Factors for Successful Family Supervision Orders: Families with Intellectual Disabilities in Child Protection in the Netherlands.

Families with mild to borderline intellectual disabilities (MBID) are overrepresented in child protection, and are at higher risk for long and unsuccessful family supervision orders (FSOs). This is worrisome, as many children apparently are exposed to unsafe parenting situations for longer periods of time. Therefore, the present study examined which child and parental factors and child maltreatment are related to the duration and success of an FSO in families with MBID in the Netherlands. Casefile data were analysed of 140 children with an ended FSO. Results from binary logistic regression analyses showed that in families with MBID, young children, children with psychiatric problems, and children with MBID were at higher risk for a longer duration of FSOs. Furthermore, young children, children with MBID and children who were sexually abused had a lower chance of a successful FSO. Unexpectedly, children who witnessed domestic violence or whose parents were divorced, had a higher chance of a successful FSO. The discussion focuses on implications of these results for treatment and care of families with MBID from the perspective of child protection.

The effect of surface roughening on the success of orthodontic mini-implants: A systematic review and meta-analysis.

INTRODUCTION: Orthodontic mini-implants are a widely accepted treatment modality in orthodontics; however, the failure rate is moderately high. Surface roughening is the golden standard in conventional oral implantology, and this may prove beneficial for orthodontic mini-implants as well. The objective of this systematic review is to assess the effect of surface roughening on the success rate of orthodontic mini-implants in both adolescent and adult patients undergoing orthodontic treatment. METHODS: Randomized studies comparing the success of surface-roughened and smooth, machined-surface orthodontic mini-implants were included. A literature search was conducted for 6 electronic databases (Pubmed/Medline, Embase, Cochrane, CINAHL, Web of Science, and Scopus), Clinical trial registry (https://www. CLINICALTRIALS: gov), and grey literature (Google Scholar). A manual search of the reference lists of included studies was performed. Two authors independently performed the screening, data extraction, risk of bias, and quality assessments. The risk of bias was assessed with the Cochrane risk-of-bias 2.0 Tool. Data were synthesized using a random effect model meta-analysis presented as a forest plot. The certainty in the body of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation tool. RESULTS: A total of 4226 unique records were screened, and 6 of these were included in the quantitative analysis. Four additional articles were selected for a secondary outcome. A total of 364 orthodontic mini-implants were included in the primary outcome analysis. There was no statistically significant effect of surface roughening on the success of orthodontic mini-implants (odds ratio = 0.63 favoring roughened orthodontic mini-implants; 95% confidence interval, 0.35-1.14). The secondary outcome (ie, the overall failure rate of roughened orthodontic mini-implants) was 6% based on studies with high heterogeneity. Limitations of this study were the risk of bias, study imprecision, and possible publication bias, leading to a very low certainty in the body of evidence. CONCLUSIONS: There is very low-quality evidence that there is no statistically significant effect of surface roughening on the success of orthodontic mini-implants in humans. The overall failure rate of surface-roughened orthodontic mini-implants was 6%. FUNDING: No funding was received for this review. REGISTRATION: This study was preregistered in the Prospective Register of Systematic Reviews (CRD42022371830).

Influence of miniscrew-assisted rapid palatal expansion (MARPE) on the interdental papilla height of maxillary central incisors.

OBJECTIVES: To evaluate the influence of miniscrew-assisted rapid palatal expansion (MARPE) on the interdental papilla height of maxillary central incisors. MATERIALS AND METHODS: Patients who completed MARPE treatment at the Radboud University Medical Center between 2018 and 2021 were included in this retrospective study. The papilla height between the maxillary central incisors was evaluated on frontal intraoral photographs taken before expansion (T0) and 1.5 years after MARPE treatment (T1) using the Jemt classification. The difference in Jemt score at T0 and T1 was the primary outcome variable. In addition, gender, age, Angle classification, MARPE duration, midpalatal suture maturation stage, maximal central diastema (MCD) immediately after expansion, crown width to length ratio (W/L), pretreatment overlap of maxillary central incisors, and the distance between the approximal contact point of the central incisors and the bone crest (CP-B) were also record. RESULTS: Twenty-two patients were included (2 men, 20 women, mean age 27.3 ± 8.8 years) and 4 patients (18%) showed a significant reduction in the Jemt score following MARPE (p = 0.04), indicating papilla recession. Interdental papilla recession was significantly associated with the increase of CP-B (p = 0.02), smaller W/L (p < 0.01), overlapping of maxillary central incisors (p < 0.01), and smaller MCD immediately after expansion (p = 0.02). CONCLUSIONS: One and a half years after MARPE, 18% of patients exhibited mild recession of papilla height of the maxillary central incisors. Overlapping and smaller W/L of maxillary central incisors were prognostic factors for interdental papilla recession. CLINICAL RELEVANCE: Clinicians have to be aware of and inform the patients about the occurrence of papilla recession following MARPE.

What is the impact of miniscrew-assisted rapid palatal expansion on the midfacial soft tissues? A prospective three-dimensional stereophotogrammetry study.

OBJECTIVES: To evaluate the midfacial soft tissue changes of the face in patients treated with miniscrew-assisted rapid palatal expansion (MARPE). MATERIALS AND METHODS: 3D facial images and intra-oral scans (IOS) were obtained before expansion (T0), immediately after completion of expansion (T1), and 1 year after expansion (T2). The 3D images were superimposed and two 3D distance maps were generated to measure the midfacial soft tissue changes: immediate effects between timepoints T0 and T1 and overall effects between T0 and T2. Changes of the alar width were also measured and dental expansion was measured as the interpremolar width (IPW) on IOS. RESULTS: Twenty-nine patients (22 women, 7 men, mean age 25.9 years) were enrolled. The soft tissue in the regions of the nose, left of philtrum, right of philtrum, and upper lip tubercle demonstrated a statistically significant anterior movement of 0.30 mm, 0.93 mm, 0.74 mm, and 0.81 mm, respectively (p < 0.01) immediately after expansion (T0-T1). These changes persisted as an overall effect (T0-T2). The alar width initially increased by 1.59 mm, and then decreased by 0.08 mm after 1 year, but this effect was not significant. The IPW increased by 4.58 mm and remained stable 1 year later. There was no significant correlation between the increase in IPW and alar width (r = 0.35, p = 0.06). CONCLUSIONS: Our findings indicate that MARPE results in significant but small changes of the soft tissue in the peri-oral and nasal regions. However, the clinical importance of these findings is limited. CLINICAL RELEVANCE: MARPE is an effective treatment modality to expand the maxilla, incurring only minimal and clinically insignificant changes to the midfacial soft tissues.

Posterior Dahl: A Minimally Invasive Method for the Treatment of Localized Posterior Tooth Wear.

PURPOSE: This retrospective case series of 9 patients aimed to describe clinical outcomes and patient satisfaction following the implementation of the posterior Dahl concept to manage localized posterior tooth wear. MATERIALS AND METHODS: Localized occlusal space was created in the posterior dentition. Supra-occluding direct restorations were placed bilaterally for the restoration of molars. Intraoral scans were taken at the pre-treatment stage, immediately post-restoration, and during follow-up appointments. Scans were used to undertake analysis of any occlusal changes and re-establishment of the occlusion. A questionnaire was used to assess patient satisfaction, alleviation of any pre-treatment concerns, and evaluation of post-treatment complaints. RESULTS: Immediately post-treatment, all patients showed an increase in the vertical dimension. Opening of the bite in the untreated areas following restoration of worn posterior molars resulted either in a tendency towards or the actual reestablishment of the occlusion. One patient completely lacked compensatory vertical tooth movement in the untreated areas, culminating in the persistence of a vertical open bite. One restoration displayed cohesive fracture after 4 months. Pre-treatment problems (eg, sensitivity) were fully resolved amongst all patients after 6 months. Post-treatment complaints were minor and demonstrated resolution within a relatively short period of time. Eight patients reported being "very satisfied" with their treatment outcomes. CONCLUSION: Application of the posterior Dahl concept appears to offer a promising, relatively simple, minimally invasive and effective approach for the management of localized posterior tooth wear, which is well accepted by patients.

Do platelet concentrates accelerate orthodontic tooth movement?: a systematic review.

PURPOSE: Surgical techniques in orthodontics have received widespread attention in recent years. Meanwhile, biomaterials with high molecular content have been introduced, such as platelet concentrates (PCs), which may accelerate orthodontic tooth movement (OTM) and reduce periodontal damage. The present systematic review aimed to answer the following PICO question: "In patients in whom orthodontic surgical techniques are performed (P), what is the effectiveness of using PCs over the surgical site (I) when compared to not placing PCs (C) to achieve faster tooth movement (O)?" METHODS: A search was performed in 6 databases. The criteria employed were those described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses declaration. The present review included studies with a control group that provided information about the influence of PCs on the rate of OTM. RESULTS: The electronic search identified 10 studies that met the established criteria. CONCLUSIONS: The included studies were very diverse, making it difficult to draw convincing conclusions. However, a tendency was observed for OTM to be accelerated when PCs were used as an adjuvant for canine distalization after premolar extraction when distalization was started in the same session. Likewise, studies seem to indicate an association between PC injection and the amount of canine retraction. However, it is not possible to affirm that the use of PCs in corticotomy shortens the overall treatment time, as this question has not been studied adequately. TRIAL REGISTRATION: PROSPERO Identifier: CRD42021278542.

What is the Oral Health-related Quality of Life following Miniscrew-Assisted Rapid Palatal Expansion (MARPE)? A prospective clinical cohort study.

BACKGROUND: Miniscrew-Assisted Rapid Palatal Expansion (MARPE) is a non-surgical orthodontic treatment for transverse maxillary deficiency. This study aimed to investigate the Oral Health-related Quality of Life (OHRQoL) and pain perception of patients undergoing MARPE treatment. METHODS: 42 consecutive patients (9 men, 33 women) from the age of 16 onwards (mean: 27.4 ± 9.3 years; range 17.1-55.7 years) who received a MARPE treatment were included. OHRQoL was assessed with the short form of the Oral Health Impact Profile (OHIP-14) questionnaire. Patients filled out the questionnaire at baseline (T0) and weekly during the expansion phase (P1) and in the post-expansion phase (P2). Pain intensity was assessed with a Visual Analogue Scale (VAS) questionnaire and filled out daily during expansion, along with a question on the intake of analgesics. The mean weekly and total OHIP-score and OHIP-score per domain were calculated at T0, P1 and P2, as well as mean weekly and total VAS-scores for average pain, maximum pain and analgesics intake during P1. Kruskal-Wallis tests were used to test for differences in OHIP between T0, P1 and P2. The level of significance was set at 0.05. RESULTS: The mean OHIP-score was 10.86 ± 9.71 at T0 and increased to 17.18 ± 10.43 during P1 (p < 0.001), after which it returned to pre-expansion levels, 9.27 ± 7.92 (p = 0.907) during P2. At the domain level, there was a statistically significant increase in OHIP-score at P1 for functional limitation, physical pain, psychological discomfort and social disability. The mean VAS-score for average pain during expansion was 16.00 ± 19.73 mm. Both OHIP-score (25.00 ± 10.25), average pain (33.72 ± 16.88 mm), maximum pain (44.47 ± 17.99 mm) and analgesics intake (59%) were highest at initiation of the expansion and decreased by the end of expansion. CONCLUSIONS: MARPE is a generally well-tolerated expansion treatment. A temporary decline in OHRQoL and moderate pain are present at the start of expansion, followed by a recovery of OHRQoL and very mild pain during the rest of treatment. Clinicians should be aware of the effects of MARPE on patients' quality of life and manage the expected discomfort and impediments with adequate communication and patient education.

Efficacy of Miniscrew-Assisted Rapid Palatal Expansion (MARPE) in late adolescents and adults with the Dutch Maxillary Expansion Device: a prospective clinical cohort study.

OBJECTIVES: To provide a higher degree of evidence on the efficacy of Miniscrew-Assisted Rapid Palatal Expansion (MARPE) in late adolescents and adults, thereby applying the Dutch Maxillary Expansion Device (D-MED). MATERIALS AND METHODS: D-MED was developed as an individualized, 3D-designed, and fabricated MARPE appliance supported by 4 palatal miniscrews. Patients from the age of 16 onwards with transverse maxillary deficiency were enrolled consecutively. Pre-expansion and immediate post-expansion CBCTs and intra-oral scans were acquired and measurements of skeletal, alveolar, and dental expansion as well as dental and periodontal side-effects were performed. RESULTS: Thirty-four patients were enrolled (8 men, 26 women) with mean age 27.0 ± 9.4 years. A success rate of 94.1% was achieved (32/34 patients). The mean expansion duration, or mean observation time, was 31.7 ± 8.0 days. The mean expansion at the maxillary first molars (M1) and first premolars (P1) was 6.56 ± 1.70 mm and 4.19 ± 1.29 mm, respectively. The expansion was 60.4 ± 20.1% skeletal, 8.1 ± 27.6% alveolar, and 31.6 ± 20.1% dental at M1 and 92.2 ± 14.5% skeletal, 0.0 ± 18.6% alveolar, and 7.8 ± 17.7% dental at P1, which was both statistically (p < 0.001) and clinically significant. Buccal dental tipping (3.88 ± 3.92° M1; 2.29 ± 3.89° P1), clinical crown height increase (0.12 ± 0.31 mm M1; 0.04 ± 0.22 mm P1), and buccal bone thinning (- 0.31 ± 0.49 mm M1; - 0.01 ± 0.45 mm P1) were observed, while root resorption could not be evaluated. CONCLUSIONS: MARPE by application of D-MED manifested its efficacy in a prospective clinical setting, delivering a high amount of skeletal expansion with limited side-effects in late adolescents and adults. CLINICAL RELEVANCE: Higher quality evidence is supportive of MARPE as a safe and successful non-surgical treatment option for transverse maxillary deficiency.

Efficacy of Miniscrew-Assisted Rapid Palatal Expansion (MARPE) in late adolescents and adults: a systematic review and meta-analysis.

BACKGROUND: Miniscrew-Assisted Rapid Palatal Expansion (MARPE) is a non-surgical treatment for transverse maxillary deficiency. However, there is limited evidence concerning its efficacy. OBJECTIVES: This systematic review aims to evaluate the efficacy of MARPE in late adolescents and adults by assessing success rate and skeletal and dental transverse maxillary expansion, as well as treatment duration, dental and periodontal side effects and soft tissue effects. SEARCH METHODS: Seven electronic databases were searched (MEDLINE, Embase, Cochrane Library, Web of Science, Scopus, ProQuest and ClinicalTrials.gov) without limitations in November 2020. SELECTION CRITERIA: Randomized and non-randomized clinical trials and observational studies on patients from the age of 16 onwards with transverse maxillary deficiency who were treated with MARPE and which included any of the predefined outcomes. DATA COLLECTION AND ANALYSIS: Inclusion eligibility screening, data extraction and risk of bias assessment were performed independently in duplicate. When possible, exploratory meta-analyses of mean differences (MDs) with their 95% confidence intervals (CIs) were conducted, followed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis of the evidence quality. RESULTS: Eight articles were included: two prospective and six retrospective observational studies. One study had a moderate risk of bias, whereas seven studies had a serious risk of bias. GRADE quality of evidence was very low. MARPE showed a high success rate (mean: 92.5%; 95%CI: 88.7%-96.3%), resulting in a significant skeletal width increase (MD: 2.33 mm; 95%CI: 1.63 mm-3.03 mm) and dental intermolar width increase (MD: 6.55 mm; 95%CI: 5.50 mm-7.59 mm). A significant increase in dental tipping, a decrease in mean buccal bone thickness and buccal alveolar height, as well as nasal soft tissue change was present (P < 0.05). The mean duration of expansion ranged from 20 to 126 days. LIMITATIONS: One of the main drawbacks was the lack of high-quality prospective studies in the literature. CONCLUSIONS AND IMPLICATIONS: MARPE is a treatment modality that is associated with a high success rate in skeletal and dental maxillary expansion. MARPE can induce dental and periodontal side effects and affect peri-oral soft tissues. Given the serious risk of bias of the included studies, careful data interpretation is necessary and future research of higher quality is strongly recommended. REGISTRATION: PROSPERO (CRD42020176618). FUNDING: No grants or any other support funding were received.

Orthodontic radiology: development of a clinical practice guideline.

OBJECTIVES: Radiographs are considered essential in orthodontics. However, their diagnostic value and indications for use are still uncertain, while exposure to radiation carries health risks. This study aimed to report on the development of a clinical practice guideline on orthodontic radiology. METHODS: A Guideline Development Taskforce was set up. The GRADE methodology was used for development and the RIGHT Statement for reporting of the guideline. We systematically reviewed articles to address the main clinical question: how different types of radiographs contribute to orthodontic diagnosis, treatment planning and post-treatment outcome evaluation. After a literature search and data extraction, we formulated conclusions and assessed the strength of the evidence according to the GRADE method. Both literature conclusions and the most important considerations, such as patient preferences, organizational matters and expert opinions were taken into account to finally issue recommendations. RESULTS: 7 clinical questions focused on orthopantomograms, lateral cephalograms, hand-wrist radiographs, peri-apical radiographs, bitewings, antero-occlusal radiographs, and cone-beam computer tomographic imaging. The literature search lead to 484 unique studies, of which 17 were included in the analysis. The strength of evidence of the conclusions was graded low or very low. We formulated considerations and took them into account when issuing the 13 clinical recommendations to address the clinical questions. CONCLUSIONS: There was a considerable lack of scientific evidence on this topic. Nonetheless, this guideline provides clinicians with a tool for decision-making regarding radiographic records while enhancing patient radiation protection. More research of higher quality is recommended for a future update.

Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells.

Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20+ B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab')2 fragments, as well as C1q-binding-deficient IgG mutants, retained an ability to induce CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted of specific complement components demonstrated that the observed lytic activity, which we termed "accessory CDC," remained to be dependent on C1 and the classical pathway. We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR- B cell lines. A direct relationship between BCR expression and accessory CDC was established by transfecting the BCR into CD20+ cells: OFA-F(ab')2 fragments were able to induce CDC in the CD20+BCR+ cell population, but not in the CD20+BCR- population. Importantly, OFA-F(ab')2 fragments were able to induce CDC ex vivo in malignant B cells isolated from patients with mantle cell lymphoma and Waldenström macroglobulinemia. In summary, accessory CDC represents a novel effector mechanism that is dependent on type I CD20 Ab-induced BCR clustering. Accessory CDC may contribute to the excellent capacity of type I CD20 Abs to induce CDC, and thereby to the antitumor activity of such Abs in the clinic.

Effectiveness of a clinical guideline to improve dental health among orthodontically treated patients: study protocol for a cluster randomized controlled trial.

BACKGROUND: White spot lesions (WSLs) occur as a side effect in over 25 % of patients who undergo orthodontic treatment, causing aesthetic problems and a risk of deeper enamel and dentine lesions. Dutch orthodontists show substantial variation in their application of WSL preventive measures, which include little incorporation of evidence from the literature. We recently developed an evidence-based clinical practice guideline (CPG) on this topic, which was further converted into a computerized clinical decision support system (CDSS) to facilitate its incorporation into clinical practice. The present study aimed to assess the effectiveness of this CPG-based CDSS, with regard to actually preventing WSL development during orthodontic treatment with fixed appliances compared to usual preventive measures. Our study also aimed to evaluate the effects of implementing the CPG-based CDSS into routine clinical practice using a multifaceted strategy. METHODS/DESIGN: We designed a hybrid effectiveness-implementation study assessing both clinical effectiveness of the CPG and its implementation into routine practice. A total of 840 patients nested in 14 orthodontic practices will be randomly assigned as clusters to the intervention or the control arm. Patients recruited by the orthodontist in the intervention group will be treated following the CPG, while the usual preventative measures will be followed in the control arm. The primary outcome measure is the proportion of patients with newly formed or enlarged WSLs after 6-9 months of treatment with fixed appliances, and at the end of treatment, using the CPG for WSL prevention compared with usual preventive measures. An additional aim is to obtain some preliminary outcomes regarding the implementation process. DISCUSSION: This study investigates the effectiveness of a newly developed guideline to improve oral health during orthodontic treatment, while simultaneously illuminating potential difficulties in adopting a guideline in general orthodontic practice. The innovative features of this study include the risk-based CDSS that discriminates between patients' oral health statuses with regard to preventive measure utilization in general orthodontic practices. Most studies focusing on WSL prevention apply the preventive intervention to each patient in an experimental setting, resulting in overtreatment and a disconnect from the real-world conditions in which the intervention is to be applied. Additionally, one of the overreaching goals of this initiative is to create a gold standard for WSL prevention during orthodontic treatment, against which future studies can compare new promising preventive measures and the readiness of clinicians to change and adopt new treatments. By doing so, we want to help bridge the gap between science and orthodontic clinical practice and improve the quality of oral health care. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Registry of the Dutch Cochrane Center under number NTR5012 , registration date 2 March 2015.

Another way of looking at treatment stability.

OBJECTIVE: To determine the contribution of normal physiological changes to the overall manifestation of a relapse after orthodontic treatment. We analyzed long-term changes in the dentition of patients with Class I malocclusions after orthodontic treatment compared with a representative group with untreated Class I malocclusions. MATERIALS AND METHODS: Study participants (n  =  66; mean age, 12 years at treatment initiation) were treated for Class I malocclusions. Dental changes were evaluated at 2, 5, 10, and 15 years after treatment. Control participants (n  =  79) had untreated Class I malocclusions (n  =  53 evaluated at ages 12 and 22 years; n  =  26 evaluated at ages 19 and 39 years). Dental changes were evaluated with the Peer Assessment Rating (PAR) index. RESULTS: In untreated and treated groups, PAR scores increased over time with gender-specific changes. In the untreated groups, the PAR score significantly increased in male participants between the ages of 12 and 22 years (P  =  .04) and in female participants between the ages of 19 and 39 years (P  =  .001). In the treated group, early posttreatment changes were primarily related to the initial treatment response. Later changes in the PAR score could be attributed to physiological changes, with the same gender-specific changes as those observed in the untreated group. CONCLUSIONS: The pattern of physiological changes in dentition for participants between the ages of 12 and 39 was different between sexes. Females showed more relapse than males between 10 and 15 years posttreatment. This distinction should be considered when evaluating long-term orthodontic treatment responses.

Complement is activated by IgG hexamers assembled at the cell surface.

Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.

Comparison of different cardiac risk scores for coronary artery disease in symptomatic women: do female-specific risk factors matter?

BACKGROUND: Cardiovascular diseases remain the leading cause of death in women and there is a need for more accurate risk assessment scores. The aims of our study were to compare the accuracy of several widely used cardiac risk assessment scores in predicting the likelihood of obstructive coronary artery disease (CAD) on CT coronary angiography (CTCA) in symptomatic women and to explore which female-specific risk factors were independent predictors of obstructive CAD on CTCA and whether adding these risk factors to pre-test probability scores would improve their predictive value. METHODS AND RESULTS: Data were obtained from a cohort of 228 consecutively included symptomatic women undergoing evaluation for CAD and referred for CTCA. Obstructive CAD was defined as ≥50% luminal stenosis on CTCA. Pre-test probability for CAD was calculated according to the Diamond and Forrester score, New score, Duke clinical score, and an updated Diamond and Forrester score. Female-specific factors were obtained by a written questionnaire. Pre-test probability scores were compared with ROC analysis and showed that only the New score and the updated Diamond and Forrester score were significant predictive scores for obstructive CAD on CTCA (area under the curve, AUC, 0.67, p < 0.01; AUC 0.61, p = 0.04, respectively). Multivariable logistic regression analysis identified that gestational diabetes mellitus (GDM) and oestrogen status were independent predictors of obstructive CAD when adjusted for the pre-test probability scores. The updated Diamond and Forrester score was used for net reclassification improvement (NRI) analysis, since the New score already accounts for oestrogen status. Adding GDM and oestrogen status to the updated Diamond and Forrester score resulted in a significant NRI (p = 0.04). CONCLUSIONS: There is a large variability in prediction of obstructive CAD using different pre-test probability risk scores in symptomatic women. Logistic regression analysis revealed that oestrogen status and GDM were independently associated with the occurrence of obstructive stenosis on CTCA. The predictive ability of cardiac pre-test probability scores improved significantly with the addition of oestrogen status and GDM.

Volumetric changes of the nose and nasal airway 2 years after tooth-borne and bone-borne surgically assisted rapid maxillary expansion.

This study aimed to assess the effects of bone-borne and tooth-borne surgically assisted rapid maxillary expansion on the volumes of the nose and nasal airway 2 yr after maxillary expansion. This prospective cohort study included 32 patients with transverse maxillary hypoplasia. Expansion was performed with a tooth-borne distractor (Hyrax) in 19 patients and with a bone-borne distractor [transpalatal distractor (TPD)] in the remaining 13. Cone beam computed tomography scans and three-dimensional (3D) photographs of the face were acquired before treatment and 22 ± 7 months later, and were used to evaluate the volumes of the nose and nasal airway. Nasal volume increased by 1.01 ± 1.6% in the Hyrax group and by 2.39 ± 2.4% in the TPD group. Nasal airway volume increased by 9.7 ± 5.6% in the Hyrax group and by 12.9 ± 12.7% in the TPD group. Changes in the nasal volume and in the nasal airway volume between the pre- and post-treatment measurements were statistically significant, whereas differences between the treatment groups were not; 22 months after surgically assisted rapid maxillary expansion, the increases in the nasal volume and in the nasal airway volume were comparable between tooth-borne and bone-borne devices.

IgA EGFR antibodies mediate tumour killing in vivo.

Currently all approved anti-cancer therapeutic monoclonal antibodies (mAbs) are of the IgG isotype, which rely on Fcgamma receptors (FcγRs) to recruit cellular effector functions. In vitro studies showed that targeting of FcαRI (CD89) by bispecific antibodies (bsAbs) or recombinant IgA resulted in more effective elimination of tumour cells by myeloid effector cells than targeting of FcγR. Here we studied the in vivo anti-tumour activity of IgA EGFR antibodies generated using the variable sequences of the chimeric EGFR antibody cetuximab. Using FcαRI transgenic mice, we demonstrated significant in vivo anti-tumour activity of IgA2 EGFR against A431 cells in peritoneal and lung xenograft models, as well as against B16F10-EGFR cells in a lung metastasis model in immunocompetent mice. IgA2 EGFR was more effective than cetuximab in a short-term syngeneic peritoneal model using EGFR-transfected Ba/F3 target cells. The in vivo cytotoxic activity of IgA2 EGFR was mediated by macrophages and was significantly decreased in the absence of FcαRI. These results support the potential of targeting FcαRI for effective antibody therapy of cancer.

Staphylococcus aureus formyl peptide receptor-like 1 inhibitor (FLIPr) and its homologue FLIPr-like are potent FcγR antagonists that inhibit IgG-mediated effector functions.

To evade opsonophagocytosis, Staphylococcus aureus secretes various immunomodulatory molecules that interfere with effective opsonization by complement and/or IgG. Immune-evasion molecules targeting the phagocyte receptors for these opsonins have not been described. In this study, we demonstrate that S. aureus escapes from FcγR-mediated immunity by secreting a potent FcγR antagonist, FLIPr, or its homolog FLIPr-like. Both proteins were previously reported to function as formyl peptide receptor inhibitors. Binding of FLIPr was mainly restricted to FcγRII receptors, whereas FLIPr-like bound to different FcγR subclasses, and both competitively blocked IgG-ligand binding. They fully inhibited FcγR-mediated effector functions, including opsonophagocytosis and subsequent intracellular killing of S. aureus by neutrophils and Ab-dependent cellular cytotoxicity of tumor cells by both neutrophils and NK cells. In vivo, treatment of mice with FLIPr-like prevented the development of an immune complex-mediated FcγR-dependent Arthus reaction. This study reveals a novel immune-escape function for S. aureus-secreted proteins that may lead to the development of new therapeutic agents in FcγR-mediated diseases.

Combined non-invasive functional and anatomical diagnostic work-up in clinical practice: the magnetic resonance and computed tomography in suspected coronary artery disease (MARCC) study.

AIMS: The combined use of cardiac computed tomography (CT) coronary angiography (CTCA) and myocardial perfusion imaging allows the non-invasive evaluation of coronary morphology and function. Cardiovascular magnetic resonance (CMR) imaging has several advantages: it can simultaneously assess myocardial perfusion, ventricular and valvular function, cardiomyopathy, and aortic disease and does not involve any additional ionizing radiation. We investigated the combined use of cardiac CT and CMR for the diagnostic evaluation of patients with suspected coronary artery disease (CAD) in clinical practice. METHODS AND RESULTS: A total of 192 patients with low or intermediate pre-test probability of CAD underwent CTCA and CMR. All patients with obstructive CAD on CTCA and/or myocardial ischaemia on CMR were referred for invasive coronary angiography (ICA). Fractional flow reserve was measured in case of intermediate lesions (30-70% diameter stenosis) on ICA. Additional cardiac and extra-cardiac findings by CTCA and CMR were registered. The combination of CTCA and CMR significantly improved specificity and overall accuracy (94 and 91%) for the detection of significant CAD compared with their use as a single technique (CTCA 39 and 57%, P < 0.0001; CMR 82 and 83%, P = 0.016). No events were recorded during follow-up (18 ± 6 months) in 104 patients who did not undergo ICA. Furthermore, the combined strategy provided an alternative diagnosis in 19 patients. CONCLUSION: The combined use of CTCA and CMR significantly improved specificity and overall diagnostic accuracy for the detection of significant CAD and allowed the detection of alternative (extra-)cardiac disease in patients without significant CAD.

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.

The promise of bispecific antibodies (bsAbs) to yield more effective therapeutics is well recognized; however, the generation of bsAbs in a practical and cost-effective manner has been a formidable challenge. Here we present a technology for the efficient generation of bsAbs with normal IgG structures that is amenable to both antibody drug discovery and development. The process involves separate expression of two parental antibodies, each containing single matched point mutations in the CH3 domains. The parental antibodies are mixed and subjected to controlled reducing conditions in vitro that separate the antibodies into HL half-molecules and allow reassembly and reoxidation to form highly pure bsAbs. The technology is compatible with standard large-scale antibody manufacturing and ensures bsAbs with Fc-mediated effector functions and in vivo stability typical of IgG1 antibodies. Proof-of-concept studies with HER2×CD3 (T-cell recruitment) and HER2×HER2 (dual epitope targeting) bsAbs demonstrate superior in vivo activity compared with parental antibody pairs.