Analysis of Randomised Trials Including Multiple Births When Birth Size Is Informative

BACKGROUND: Informative birth size occurs when the average outcome depends on the number of infants per birth. Although analysis methods have been proposed for handling informative birth size, their performance is not well understood. Our aim was to evaluate the performance of these methods and to provide recommendations for their application in randomised trials including infants from single and multiple births. METHODS: Three generalised estimating equation (GEE) approaches were considered for estimating the effect of treatment on a continuous or binary outcome: cluster weighted GEEs, which produce treatment effects with a mother-level interpretation when birth size is informative; standard GEEs with an independence working correlation structure, which produce treatment effects with an infant-level interpretation when birth size is informative; and standard GEEs with an exchangeable working correlation structure, which do not account for informative birth size. The methods were compared through simulation and analysis of an example dataset. RESULTS: Treatment effect estimates were affected by informative birth size in the simulation study when the effect of treatment in singletons differed from that in multiples (i.e. in the presence of a treatment group by multiple birth interaction). The strength of evidence supporting the effectiveness of treatment varied between methods in the example dataset. CONCLUSIONS: Informative birth size is always a possibility in randomised trials including infants from both single and multiple births, and analysis methods should be pre-specified with this in mind. We recommend estimating treatment effects using standard GEEs with an independence working correlation structure to give an infant-level interpretation

A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly

Background: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. Methods: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. Results: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. Conclusion: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. Trial Registration: The Australian Clinical Trials Registry ACTRN12607000387426 © 2014 MacIntyre et al

Can HRCT be used as a marker of airway remodelling in children with difficult asthma?

BACKGROUND: Whole airway wall thickening on high resolution computed tomography (HRCT) is reported to parallel thickening of the bronchial epithelial reticular basement membrane (RBM) in adult asthmatics. A similar relationship in children with difficult asthma (DA), in whom RBM thickening is a known feature, may allow the use of HRCT as a non-invasive marker of airway remodelling. We evaluated this relationship in children with DA. METHODS: 27 children (median age 10.5 [range 4.1-16.7] years) with DA, underwent endobronchial biopsy from the right lower lobe and HRCT less than 4 months apart. HRCTs were assessed for bronchial wall thickening (BWT) of the right lower lobe using semi-quantitative and quantitative scoring techniques. The semi-quantitative score (grade 0-4) was an overall assessment of BWT of all clearly identifiable airways in HRCT scans. The quantitative score (BWT %; defined as [airway outer diameter - airway lumen diameter]/airway outer diameter x100) was the average score of all airways visible and calculated using electronic endpoint callipers. RBM thickness in endobronchial biopsies was measured using image analysis. 23/27 subjects performed spirometry and the relationships between RBM thickness and BWT with airflow obstruction evaluated. RESULTS: Median RBM thickness in endobronchial biopsies was 6.7(range 4.6-10.0) microm. Median qualitative score for BWT of the right lower lobe was 1(range 0-1.5) and quantitative score was 54.3 (range 48.2-65.6)%. There was no relationship between RBM thickness and BWT in the right lower lobe using either scoring technique. No relationship was found between FEV1 and BWT or RBM thickness. CONCLUSION: Although a relationship between RBM thickness and BWT on HRCT has been found in adults with asthma, this relationship does not appear to hold true in children with D

Perforated Meckel diverticulum

Perforation of a Meckel diverticulum (MD) is a rare complication that can often mimic appendicitis. This case report identifies a child who presented to our Emergency Department (ED) with right lower quadrant abdominal pain, free fluid and air in the abdomen and pelvis, and inflammatory changes visualized on Ultrasonography (US) and computer tomography (CT) scan. In our patient, ruptured appendicitis was suspected, and the diagnosis of ruptured MD was ultimately made by laparoscopy. This case demonstrates that a healthy degree of suspicion for complicated MD should be present when dealing with a questionable diagnosis of appendicitis, particularly in the pediatric population

Enhancement of electroporation facilitated immunogene therapy via T-reg depletion

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival

Laparoscopic treatment of isolated superficial peritoneal endometriosis for managing chronic pelvic pain in women:study protocol for a randomised controlled feasibility trial (ESPriT1)

Background: Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. Three subtypes of endometriosis exist, with ~ 80% of women having superficial peritoneal endometriosis (SPE). Endometriosis is diagnosed by laparoscopy and, if SPE is found, gynaecologists usually remove it surgically. However, many women get limited pain relief from surgical removal of SPE. We plan to undertake a future large trial where women who have only SPE found at initial laparoscopy are randomly allocated to have surgical removal (excision or ablation) of SPE, or not. Ultimately, we want to determine whether surgical removal improves overall symptoms and quality of life, or whether surgery is of no benefit, exacerbates symptoms, or even causes harm. The primary objective of this feasibility study is to determine what proportion of women with suspected SPE undergoing diagnostic laparoscopy will agree to randomisation. The secondary objectives are to determine if there are differences in key prognostic parameters between eligible women that agree to be randomised and those that decline; how many women having laparoscopy for investigation of chronic pelvic pain are eligible for the trial; the range of treatment effects and variability in outcomes and the most acceptable methods of recruitment, randomisation and assessment tools. Methods: We will recruit up to 90 women with suspected SPE undergoing diagnostic laparoscopy over a 9-month recruitment period in four Scottish hospitals and randomise them 1:1 to either diagnostic laparoscopy alone (with a sham port to achieve blinding of the allocation) or surgical removal of endometriosis. Baseline characteristics, e.g. age, index of social deprivation, ethnicity, and intensity/duration of pain will be collected. Participants will be followed up by online questionnaires assessing pain, physical and emotional function at baseline, 3 months, 6 months and 12 months. Discussion: Recruitment to a randomised controlled trial to assess the effectiveness of surgery for endometriosis may be challenging because of preconceived ideas about treatment success amongst patients and clinicians. We have designed this study to assess feasibility of recruitment and to inform the design of our future definitive trial. Trial registration: ClincicalTrials.gov, NCT04081532 Status: Recruiting

International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide

Chiral U(1) flavor models and flavored Higgs doublets: the top FB asymmetry and the Wjj

We present U(1) flavor models for leptophobic Z' with flavor dependent couplings to the right-handed up-type quarks in the Standard Model, which can accommodate the recent data on the top forward-backward (FB) asymmetry and the dijet resonance associated with a W boson reported by CDF Collaboration. Such flavor-dependent leptophobic charge assignments generally require extra chiral fermions for anomaly cancellation. Also the chiral nature of U(1)' flavor symmetry calls for new U(1)'-charged Higgs doublets in order for the SM fermions to have realistic renormalizable Yukawa couplings. The stringent constraints from the top FB asymmetry at the Tevatron and the same sign top pair production at the LHC can be evaded due to contributions of the extra Higgs doublets. We also show that the extension could realize cold dark matter candidates.Comment: 40 pages, 10 figures, added 1 figure and extended discussion, accepted for publication in JHE