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Acute myeloid leukemia (AML) patients with minimal residual disease and receiving allogeneic hematopoietic stem cell transplantation (HCT) have poor survival. Adoptive administration of dendritic cells (DCs) presenting the Wilms tumor protein 1 (WT1) leukemia-associated antigen can potentially stimulate de novo T and B cell development to harness the graft-versus-leukemia (GvL) effect after HCT. We established a simple and fast genetic modification of monocytes for simultaneous lentiviral expression of a truncated WT1 antigen (tWT1), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-α, promoting their self-differentiation into potent “induced DCs” (iDCtWT1). A tricistronic integrase-defective lentiviral vector produced under good manufacturing practice (GMP)-like conditions was validated. Transduction of CD14+ monocytes isolated from peripheral blood, cord blood, and leukapheresis material effectively induced their self-differentiation. CD34+ cell-transplanted Nod.Rag.Gamma (NRG)- and Nod.Scid.Gamma (NSG) mice expressing human leukocyte antigen (HLA)-A∗0201 (NSG-A2)-immunodeficient mice were immunized with autologous iDCtWT1. Both humanized mouse models showed improved development and maturation of human T and B cells in the absence of adverse effects. Toward clinical use, manufacturing of iDCtWT1 was up scaled and streamlined using the automated CliniMACS Prodigy system. Proof-of-concept clinical-scale runs were feasible, and the 38-h process enabled standardized production and high recovery of a cryopreserved cell product with the expected identity characteristics. These results advocate for clinical trials testing iDCtWT1 to boost GvL and eradicate leukemia., Graphical abstract, Hematopoietic stem cell transplantation (HCT) is used to treat acute myeloid leukemia (AML). We developed lentivirus-induced dendritic cells expressing immunomodulatory cytokines and truncated WT1 (iDCtWT1). The cells were produced in a GMP-compliant automated process to immunize AML patients after HCT.

Meta-analysis is usually performed using aggregate data. Aggregate data refer to the summary of individual participant data (IPD) on the investigated outcomes and related characteristics obtained from the trial reports. In the case of binary outcome data, the aggregate data include the number of participants who experienced the event (eg, bond failures per treatment group) from the total randomized in the trial. For continuous outcomes, such as overjet, intercanine, and intermolar width or space closure in millimeters, the researcher extracts the number of participants, the mean and standard deviation of the outcome measured in each trial arm. In terms of characteristics, aggregate data can include the summary of participant- and clinical-related characteristics, such as the mean age, gender distribution across arms, and the mean follow-up period. Although aggregate data allow for a straightforward analysis, they cannot always uncover the true associations between treatment effects and characteristics. Over time, the well-documented limitations of aggregate data analysis have initiated a paradigm shift for collecting and re-analyzing IPD, whenever possible, after the principles and procedures of conventional systematic reviews.1,2 Systematic reviews of IPD have gained popularity in the therapeutic, diagnostic, and prognostic research in numerous health care fields.3

BACKGROUND Systematic reviews have established the short-term improvements of periodontal regenerative/reconstructive procedures compared to conventional surgical treatment in intrabony defects. However, a hierarchy of periodontal regenerative/reconstructive procedures regarding the medium- to long-term results of treatment does not exist. AIM To systematically assess the literature to answer the focused question "In periodontitis patients with intrabony defects, what are the medium- and long-term benefits of periodontal regenerative/reconstructive procedures compared with open flap debridement (OFD), in terms of clinical and/or radiographic outcome parameters and tooth retention?". MATERIAL & METHODS Randomized controlled clinical trials (RCTs), reporting on clinical and/or radiographic outcome parameters of periodontal regenerative/reconstructive procedures ���3��years post-operatively, were systematically assessed. Clinical [residual probing pocket depth (PD) and clinical attachment level (CAL) gain, tooth loss] and radiographic [residual defect depth (RDD), bone gain (RBL)] outcome parameters were assessed. Descriptive statistics were calculated, and Bayesian random-effects network meta-analyses (NMA) were performed where possible. RESULTS Thirty RCTs, presenting data 3 to 20��years after treatment with grafting, GTR, EMD, as monotherapies, combinations thereof, and/or adjunctive use of blood-derived growth factor constructs or with OFD only, were included. NMA based on 21 RCTs showed that OFD was clearly the least efficacious treatment; regenerative/reconstructive treatments resulted in significantly shallower residual PD in 4 out 8 comparisons [range of mean differences (MD): -2.37 to -0.60��mm] and larger CAL gain in 6 out 8 comparisons (range of MD: 1.26 to 2.66��mm), and combination approaches appeared as the most efficacious. Tooth loss after regenerative/reconstructive treatment was less frequent (0.4%) compared to OFD (2.8%), but the evidence was sparse. There were only sparse radiographic data not allowing any relevant comparisons. CONCLUSION Periodontal regenerative/reconstructive therapy in intrabony defects results, in general, in shallower residual PD and larger CAL gain compared with OFD, translating in high rates of tooth survival, on a medium (3-5��years) to long-term basis (5-20��years). Combination approaches appear, in general, more efficacious compared to monotherapy in terms of shallower residual PD and larger CAL gain. A clear hierarchy could, however, not be established due to limited evidence.

Background Atopic dermatitis (AD) is an inflammatory chronic condition that affects the skin of children and adults and has an important impact on the quality of life. Treatments for AD are based on environmental controls, topical and systemic therapies, and allergen-specific immunotherapy (AIT). However, it remains unclear the effectiveness and adverse events of AIT and all conventional topical treatments compared with placebo and each other for AD. Methods We will search five electronic databases [Central Cochrane register of controlled trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and LILACS] from inception until November 2019 with no language restriction, and we will include experimental studies [randomized controlled trials (RCTs), and quasi-RCTs]. The primary outcome is global and specific skin symptoms assessment. Secondary outcomes are hospital length of stay, quality of life, and adverse events. Reviewers independently will extract data from the studies that meet our inclusion criteria and will assess the risk of bias of individual primary studies. We will conduct random effects pairwise meta-analyses for the observed pairwise comparisons with at least two trials. Then, we will perform random-effects Bayesian network meta-analysis (NMA) to obtain treatment effects for all possible comparisons and to provide a hierarchy of all interventions for each outcome. Possible incoherence between direct and indirect sources of evidence will be investigated locally (if possible) and globally. To investigate sources of statistical heterogeneity, we will perform a series of meta-regression analyses based on pre-specified important effect modifiers. Two authors will appraise the certainty of the evidence for each outcome applying the GRADE’s framework for NMA. Discussion The findings of this systematic review will shed the light on the effectiveness and adverse events of all possible comparisons for treating AD and on the quality of the collated evidence for recommendations. It will also provide critical information to health care professionals to comprehend and manage this disease at different age stages, treatment type, duration, and severity of atopic dermatitis. Systematic review registration PROSPERO Protocol ID CRD42019147106

Objectives To evaluate microstructural cerebral changes in children with neurofibromatosis type 1 (NF1) based on T2 relaxation time measurements at 3Tesla. Methods From our dataset of pediatric MRI examinations at 3T 19 pediatric NF1 patients (1.9–14.3 years of age, 9 girls, 10 boys) were retrospectively selected and compared with the previously published group of 44 healthy children (0–16 years of age). MRI examination included a triple echo TSE sequence as basis for T2 maps. T2 relaxation times were measured in 37 brain regions. Results Compared with healthy controls, T2 relaxation times had the tendency to be increased by 1.01% (GM) to 11.85% (dentate nucleus) for NF1 patients. Only in posterior limb of the internal capsule and parietooccipital white matter values were reduced. No differences were observed between both hemispheres. Overall, no strong evidence supporting a difference between NF1 patients with and without optic glioma or with normal and impaired neuropsychological development was observed. Conclusions Using T2 relaxation times it was possible to describe measurable microstructural differences in multiple brain regions between NF1 patients and healthy children regardless of whether signal abnormalities were visible on conventional images.

Objective To examine age-related changes in T2 relaxation times during infancy and childhood in order to assess T2 values obtained from routine MRI as a biomarker. Methods From our pool of clinical pediatric MRI examinations at 3 T all patients with normal conventional MRI scans were retrospectively selected. Depending on their clinical findings the identified 99 patients (0–199 months) were divided into 43 healthy controls and 56 diseased children with various clinical abnormalities (developmental delay, epilepsy, prematurity, and deafness). T2 maps based on routinely performed triple echo turbo spin echo sequences were created. T2 values were measured in 22 brain regions to determine age-related changes. We also investigated whether such changes differ between healthy and diseased children. Results Age significantly reduced T2 relaxation times across all regions (p Conclusions Using T2 maps based on clinical MRI data we could determine age-related T2 relaxation times in 22 brain regions during infancy and childhood. Our data have relevance for future investigator independent T2 relaxation time measurements in determining whether T2 values are within the normal range or should be considered as potentially pathologic.

The purpose of this study was to examine age-related, infratentorial changes in T2 relaxation times during infancy and childhood using routine MRI data at 3 Tesla. One hundred patients (0–199 months) without signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations. T2 maps based on our routinely acquired triple-echo turbo spin-echo (TSE) sequence were created. Based on their clinical symptoms, the children were divided into 43 controls and 57 diseased children with different clinical diseases. T2 relaxation times were measured in 15 infratentorial brain regions (medullary pyramid, ventral and dorsal pons, middle cerebellar peduncle, dentate nucleus, medial and lateral cerebellar hemisphere each on both sides, and in the cerebellar vermis) investigating age-related changes. Secondly, this study examined whether those changes in T2 values differed between healthy and diseased children. Age significantly reduced T2 relaxation time in all infratentorial brain regions (p 0.05) apart from the dentate nucleus and cerebellar hemispheres in terms of rapid decline (larger in controls) and the right dorsal pons and left pyramid in terms of slow decline (larger in diseased children). In both groups, the later slow decline was almost negligible. Using T2 maps, it was possible to determine age-related T2 relaxation times in the different infratentorial brain regions in this preliminary study. Between neurologically healthy controls and diseased children, no significant differences in T2 relaxation times could be found overall in the studied regions.

Meta-regression is simply the extension of the regression analysis. Whereas in the regression analysis, the outcome and the covariates are measured for each subject, in meta-regression, the outcome and the covariates are measured on the level of the study. Because studies differ at least in the sample size, we need to assign a weight in each study under a specific model (fixed-effect or random-effects model) before implementing a meta-regression analysis. Weight assignment is not addressed in a regression analysis, because we study subjects. The differences between the regression and the meta-regression analysis are obvious, but the goal is the same: to assess the association between an outcome and one or more covariates.

BACKGROUND: In children, functional daytime urinary incontinence is the term used to describe any leakage of urine while awake that is not the result of a known underlying neurological or congenital anatomic cause (such as conditions or injuries that affect the nerves that control the bladder or problems with the way the urinary system is formed). It can result in practical difficulties for both the child and their family and can have detrimental effects on a child’s well‐being, education and social engagement. OBJECTIVES: To assess the effects of conservative interventions for treating functional daytime urinary incontinence in children. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains studies identified from CENTRAL, MEDLINE, MEDLINE In‐Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 11 September 2018). We also searched Chinese language bibliographic databases: Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang. No language restrictions were imposed. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi‐randomised, multi‐arm studies, cross‐over studies and cluster‐randomised studies that included children aged between 5 and 18 years with functional daytime urinary incontinence. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records and determined the eligibility of studies for inclusion according to predefined criteria. Where data from the study were not provided, we contacted the study authors to request further information. Two review authors assessed risk of bias and processed included study data as described in the Cochrane Handbook for Systematic Reviews of Interventions. Where meta‐analysis was possible, we applied random‐effects meta‐analysis using the Mantel‐Haenszel method for dichotomous outcomes. MAIN RESULTS: The review included 27 RCTs involving 1803 children. Of these, six were multi‐arm and one was also a cross‐over study. Most studies were small, with numbers randomised ranging from 16 to 202. A total of 19 studies were at high risk of bias for at least one domain. Few studies reported data suitable for pooling due to heterogeneity in interventions, outcomes and measurements. Individual conservative interventions (lifestyle, behavioural or physical) versus no treatment Transcutaneous electrical nerve stimulation (TENS) versus sham (placebo) TENS. More children receiving active TENS may achieve continence (risk ratio (RR) 4.89, 95% confidence interval (CI) 1.68 to 14.21; 3 studies; n = 93; low‐certainty evidence). One individual conservative intervention versus another individual or combined conservative intervention Pelvic floor muscle training (PFMT) with urotherapy versus urotherapy alone. We are uncertain whether more children receiving PFMT with urotherapy achieve continence (RR 2.36, 95% CI 0.65 to 8.53, 95% CI 25 to 100; 3 studies; n = 91; very low‐certainty evidence). Voiding education with uroflowmetry feedback and urotherapy versus urotherapy alone. Slightly more children receiving voiding education with uroflow feedback and urotherapy may achieve continence (RR 1.13, 95% CI 0.87 to 1.45; 3 studies; n = 151; low‐certainty evidence). Urotherapy with timer watch versus urotherapy alone. We are uncertain whether urotherapy plus timer watch increases the number of children achieving continence compared to urotherapy alone (RR 1.42, 95% CI 1.12 to 1.80; 1 study; n = 58; very low‐certainty evidence). Combined conservative interventions versus other combined conservative interventions TENS and standard urotherapy versus PFMT with electromyographic biofeedback and standard urotherapy. We are uncertain whether there is any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 1.11, 95% CI 0.73 to 1.68; 1 study; n = 78; very low‐certainty evidence). PFMT with electromyography biofeedback and standard urotherapy versus PFMT without feedback but with standard urotherapy. We are uncertain whether there is any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 1.05, 95% CI 0.72 to 1.52; 1 study; n = 41; very low‐certainty evidence). Individual conservative interventions versus non‐conservative interventions (pharmacological or invasive, combined or not with any conservative interventions) PFMT versus anticholinergics. We are uncertain whether more children receiving PFMT than anticholinergics achieve continence (RR 1.92, 95% CI 1.17 to 3.15; equivalent to an increase from 33 to 64 per 100 children; 2 studies; n = 86; very low‐certainty evidence). TENS versus anticholinergics. We are uncertain whether there was any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 0.81, 95% CI 0.05 to 12.50; 2 studies; n = 72; very low‐certainty evidence). Combined conservative interventions versus non‐conservative interventions (pharmacological or invasive, combined or not with any conservative interventions) Voiding education with uroflowmetry feedback versus anticholinergics. We are uncertain whether there was any evidence of a difference between treatment groups in the proportion of children achieving continence (RR 1.02, 95% CI 0.58 to 1.78; 1 study; n = 64; very low‐certainty evidence). AUTHORS' CONCLUSIONS: The review found little reliable evidence that can help affected children, their carers and the clinicians working with them to make evidence‐based treatment decisions. In this scenario, the clinical experience of individual clinicians and the support of carers may be the most valuable resources. More well‐designed research, with well‐defined interventions and consistent outcome measurement, is needed.

OBJECTIVES The primary objective of this study was to examine the association between the first assessed cervical dilatation in a labourward and the use of oxytocin augmentation during labour. Further analysis was performed by examining the actual stage of labour at the point oxytocin was first administered to those women. DESIGN Retrospective cohort study with the data collected from the medical records of the hospital. SETTING University Hospital Bern, Switzerland PARTICIPANTS: 1933 term nulliparous and multiparous women with a singleton pregnancy giving birth during the period June 2013 and May 2017, representing Robson groups 1 and 3. MEASUREMENTS AND FINDINGS Descriptive statistics and multivariable logistic regression models were performed. It was found that for the entire process of labour, nulliparous and multiparous women (n = 1933) with a first cervical dilatation of 5 or more cm were less likely to be augmented with oxytocin (OR 0.64, 95% CI 0.46; 0.88 and OR 0.56, 95% CI 0.38; 0.82, respectively) compared to women with a first cervical dilatation of less than 5 cm. Out of these augmented women (n = 746) having a first cervical dilatation of 5 or more cm, they had a lower likelihood of being augmented during the first stage of labour compared to women with a first cervical dilatation of less than 5 cm (OR 0.45, 95% CI 0.29; 0.7 for nulliparae and OR 0.32, 95% CI 0.16; 0.6 for multiparae). Additionally, it was observed that other factors contributed to the application of oxytocin. One such example was that epidural analgesia was associated with a high risk of oxytocin augmentation in nulliparae (OR 13.88, 95% CI 9.29; 20.74) and multiparae (OR 15.52, 95% CI 9.94; 24.22). The application of oxytocin was also found to affect the caesarean section rate in nulliparous and multiparous women as it was 20% and 13% respectively for those with oxytocin versus 13% and 4% respectively for those without oxytocin. KEY CONCLUSIONS Early admission to the labourward is associated with an increased use of oxytocin to augment labour, particularly, during the first stage of labour. Epidural analgesia is a main predictor for oxytocin augmentation in nulliparous and multiparous women. IMPLICATIONS FOR PRACTICE Pregnant women warrant more appropriate support during early labour, avoiding early maternal exhaustion and excessive obstetrical interventions.

Missing outcome data are common in clinical trials and despite a well-designed study protocol, some of the randomized participants may leave the trial early without providing any or all of the data, or may be excluded after randomization. Premature discontinuation causes loss of information, potentially resulting in attrition bias leading to problems during interpretation of trial findings. The causes of information loss in a trial, known as mechanisms of missingness, may influence the credibility of the trial results. Analysis of trials with missing outcome data should ideally be handled with intention to treat (ITT) rather than per protocol (PP) analysis. However, true ITT analysis requires appropriate assumptions and imputation of missing data. Using a worked example from a published dental study, we highlight the key issues associated with missing outcome data in clinical trials, describe the most recognized approaches to handling missing outcome data, and explain the principles of ITT and PP analysis.

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch), Background: Worldwide, 14.9 million infants (11%) are born preterm each year. Up to 40% of preterm births (PTBs) are associated with genital tract infections. The vaginal pH can reflect changes in the vaginal milieu and, if elevated, indicates an abnormal flora or infection. Objective: The aim of the study was to investigate whether an increased antenatal vaginal pH >4.5 in pre-labour pregnant women is associated with an increased PTB rate 4.5 may be associated with a higher risk for PTB. It is recommended to conduct a randomised controlled trial (RCT) to investigate the effectiveness of antenatal pH screening to prevent PTB. Tweetable abstract Pregnant women with an increased vaginal pH >4.5 may be at higher risk to experience preterm birth.

OBJECTIVES The purpose of the study was to provide empirical evidence about the reporting of methodology to address missing outcome data and the acknowledgement of their impact in Cochrane systematic reviews in the mental health field. METHODS Systematic reviews published in the Cochrane Database of Systematic Reviews after January 1, 2009 by three Cochrane Review Groups relating to mental health were included. RESULTS One hundred ninety systematic reviews were considered. Missing outcome data were present in at least one included study in 175 systematic reviews. Of these 175 systematic reviews, 147 (84%) accounted for missing outcome data by considering a relevant primary or secondary outcome (e.g., dropout). Missing outcome data implications were reported only in 61 (35%) systematic reviews and primarily in the discussion section by commenting on the amount of the missing outcome data. One hundred forty eligible meta-analyses with missing data were scrutinized. Seventy-nine (56%) of them had studies with total dropout rate between 10 and 30%. One hundred nine (78%) meta-analyses reported to have performed intention-to-treat analysis by including trials with imputed outcome data. Sensitivity analysis for incomplete outcome data was implemented in less than 20% of the meta-analyses. CONCLUSIONS Reporting of the techniques for handling missing outcome data and their implications in the findings of the systematic reviews are suboptimal.

Objectives Tο report challenges encountered during the extraction process from Cochrane reviews in mental health and Campbell reviews and to indicate their implications on the empirical performance of different methods to handle missingness. Methods We used a collection of meta-analyses on binary outcomes collated from a previous work on missing outcome data. To evaluate the accuracy of their extraction, we developed specific criteria pertaining to the reporting of missing outcome data in systematic reviews. Using the most popular methods to handle missing binary outcome data, we investigated the implications of the accuracy of the extracted meta-analysis on the random-effects meta-analysis results. Results Of 113 meta-analyses from Cochrane reviews, 60 (53%) were judged as “unclearly” extracted (ie, no information on the outcome of completers but available information on how missing participants were handled) and 42 (37%) as “unacceptably” extracted (ie, no information on the outcome of completers as well as no information on how missing participants were handled). For the remaining meta-analyses, it was judged that data were “acceptably” extracted (ie, information on the completers' outcome was provided for all trials). Overall, “unclear” extraction overestimated the magnitude of the summary odds ratio and the between-study variance and additionally inflated the uncertainty of both meta-analytical parameters. The only eligible Campbell review was judged as “unclear.” Conclusions Depending on the extent of missingness, the reporting quality of the systematic reviews can greatly affect the accuracy of the extracted meta-analyses and by extent, the empirical performance of different methods to handle missingness.

Summary Background The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. Methods We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. Findings We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Interpretation Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. Funding None.

This study evaluated the diagnostic value of D-dimer, CRP, and leucocytes count to detect an underlying pulmonary embolism (PE) in patients with pneumonia. A predictive model of an underlying PE, based on laboratory markers and clinical symptoms, was our ultimate objective. Overall 100 patients underwent a computed tomography angiography (CTA) of the lung: 54 with coexistence of PE and pneumonia (cases) and 46 with pneumonia without PE (controls). Cases and controls were matched 1 : 1. Symptoms and paraclinical findings were registered on admission. Receiver operating characteristic (ROC) curves, search for an optimal threshold, and conditional logistic regression analysis were conducted. D-dimer has a moderate ability to detect PE in pneumonia. Sensitivity of D-dimer was estimated at 97.78% and specificity at 11.11%. No optimal cut-point has acceptable diagnostic ability. After excluding patients with sepsis, sensitivity was reduced to 96.97%, whereas specificity increased to 16.13%. Consolidation in chest X-ray and positive D-dimer predict better an underlying PE as D-dimer itself. Thus, discriminatory power of the prediction model (AUC of 0.740) is not much greater than D-dimer (AUC of 0.703). No threshold that could increase the diagnostic value of D-dimer or a prediction model which is significantly better than D-dimer itself was identified.

AIM To assess the risk of bias (RoB) in a subset of randomized controlled trials (RCTs) published in orthodontic journals using the Cochrane RoB tool and to identify associations between domain RoB assessment and treatment effect estimates. MATERIALS AND METHODS Fifty consecutive issues of four major orthodontic journals were electronically searched to identify RCTs. The quality of the included studies was assessed using the Cochrane RoB tool, which involves seven domains rated as 'low', 'unclear' or 'high': random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting, and other threats to internal validity. Estimates and confidence intervals (CIs) were recorded or calculated where possible for binary and continuous outcome measures. Meta-regression models were employed to assess the impact of RoB per domain on the magnitude of treatment effect. RESULTS One hundred and one eligible studies involving 128 pair-wise comparisons were retrieved. Blinding of outcome assessors and incomplete outcome data were frequently judged as 'high' for RoB both for studies with binary and continuous outcome (42.9 and 48.8 per cent, respectively). For binary outcomes, high RoB regarding random sequence generation [odds ratio (OR): 5.97, 95% CI: 2.03, 17.63, P-value: 0.002] and incomplete outcome data (OR: 4.07, 95% CI: 1.03, 16.15, P-value: 0.05) were more likely to provide exaggerated effect estimates. CONCLUSIONS There is a need for improved clinical trial methodology and reporting, in order to avoid inflated associations and erroneous conclusions.

Animal and human studies suggest that vitamin D regulates functions of the reproductive system. Vitamin D deficiency is prevalent in women of reproductive age. Vitamin D status has been associated with in vitro fertilisation outcome, features of polycystic ovarian syndrome (PCOS) and endometriosis. The aims of our study were to investigate the prevalence of vitamin D deficiency of infertile women living in central Germany, to identify risk factors for vitamin D deficiency and to specify seasonal variations of vitamin D status. This was a retrospective cohort study at an academic tertiary care centre (N = 113) and an Outpatient Centre for Reproductive Medicine (N = 193) of women presenting for infertility treatment. The statistical evaluation was descriptive and explorative. Possible risk factors associated with an increased risk for vitamin D deficiency were assessed using multiple logistic regression models. Variables with p value less than 0.05 were further assessed in a multivariable logistic regression model. Overall, 98.2 % of patients at centre 1 and 81.3 % of women with impaired fertility at centre 2 had deficient or insufficient vitamin D levels. Overweight BMI and limited exposure to sun (winter, spring and autumn trimester) were associated with an increased risk of vitamin D deficiency. Vitamin D levels did not vary according to age or infertility associated disorders (e.g. endometriosis, PCOS). The rate of vitamin D deficiency among women with impaired fertility is alarming. Prospective studies are pressingly needed to confirm a causal relationship and to investigate the potential therapeutic benefits of vitamin D supplementation in this population.

The gender gap: discrepant human T-cell reconstitution after cord blood stem cell transplantation in humanized female and male mice

Systematic reviews of well-designed trials constitute a high level of scientific evidence and are important for medical decision making. Meta-analysis facilitates integration of the evidence using a transparent and systematic approach, leading to a broader interpretation of treatment effectiveness and safety than can be attained from individual studies. Traditional meta-analyses are limited to comparing just 2 interventions concurrently and cannot combine evidence concerning multiple treatments. A relatively recent extension of the traditional meta-analytical approach is network meta-analysis, which allows, under certain assumptions, the quantitative synthesis of all evidence under a unified framework and across a network of all eligible trials. Network meta-analysis combines evidence from direct and indirect information via common comparators; interventions can therefore be ranked in terms of the analyzed outcome. In this article, the network meta-analysis approach is introduced in a nontechnical manner using a worked example on the treatment effectiveness of conventional and self-ligating appliances.

Summary Background Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs. Methods We systematically reviewed 68 randomised controlled trials (16 073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat. Findings Haloperidol (standardised mean difference [SMD] −0·56 [95% CI −0·69 to −0·43]), risperidone (–0·50 [–0·63 to −0·38), olanzapine (–0·43 [–0·54 to −0·32], lithium (–0·37 [–0·63 to −0·11]), quetiapine (–0·37 [–0·51 to −0·23]), aripiprazole (–0·37 [–0·51 to −0·23]), carbamazepine (–0·36 [–0·60 to −0·11], asenapine (–0·30 [–0·53 to −0·07]), valproate (–0·20 [–0·37 to −0·04]), and ziprasidone (–0·20 [–0·37 to −0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD −0·19 [95% CI −0·36 to −0·01]), quetiapine (–0·19 [–0·37 to 0·01]), aripiprazole (–0·19 [–0·36 to −0·02]), carbamazepine (–0·20 [–0·36 to −0·01]), asenapine (–0·26 [–0·52 to 0·01]), valproate (–0·36 [–0·56 to −0·15]), ziprasidone −0·36 [–0·56 to −0·15]), lamotrigine (–0·48 [–0·77 to −0·19]), topiramate (–0·63 [–0·84 to −0·43]), and gabapentin (–0·88 [−1·40 to −0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin. Interpretation Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines. Funding None.

Importance There is debate about the effectiveness of psychiatric treatments and whether pharmacotherapy or psychotherapy should be primarily used. Objectives To perform a systematic overview on the efficacy of pharmacotherapies and psychotherapies for major psychiatric disorders and to compare the quality of pharmacotherapy and psychotherapy trials. Evidence Review We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library (April 2012, with no time or language limit) for systematic reviews on pharmacotherapy or psychotherapy vs placebo, pharmacotherapy vs psychotherapy, and their combination vs either modality alone. Two reviewers independently selected the meta-analyses and extracted efficacy effect sizes. We assessed the quality of the individual trials included in the pharmacotherapy and psychotherapy meta-analyses with the Cochrane risk of bias tool. Findings The search yielded 45 233 results. We included 61 meta-analyses on 21 psychiatric disorders, which contained 852 individual trials and 137 126 participants. The mean effect size of the meta-analyses was medium (mean, 0.50; 95% CI, 0.41-0.59). Effect sizes of psychotherapies vs placebo tended to be higher than those of medication, but direct comparisons, albeit usually based on few trials, did not reveal consistent differences. Individual pharmacotherapy trials were more likely to have large sample sizes, blinding, control groups, and intention-to-treat analyses. In contrast, psychotherapy trials had lower dropout rates and provided follow-up data. In psychotherapy studies, wait-list designs showed larger effects than did comparisons with placebo. Conclusions and Relevance Many pharmacotherapies and psychotherapies are effective, but there is a lot of room for improvement. Because of the multiple differences in the methods used in pharmacotherapy and psychotherapy trials, indirect comparisons of their effect sizes compared with placebo or no treatment are problematic. Well-designed direct comparisons, which are scarce, need public funding. Because patients often benefit from both forms of therapy, research should also focus on how both modalities can be best combined to maximize synergy rather than debate the use of one treatment over the other.