Incidence, causes and correlates of maternal near-miss morbidity: a multi-centre cross-sectional study.

OBJECTIVE: To explore the incidence and factors associated with maternal near-miss. DESIGN: Cross-sectional study with an embedded case-control study. SETTING: Three tertiary referral hospitals in southern Ghana. POPULATION: All women admitted to study facilities with pregnancy-related complications or for birth. METHODS: An adapted version of the WHO Maternal Near Miss Screening Tool was used to identify maternal near-miss cases. These were compared with unmatched controls (uncomplicated deliveries) in a ratio of 1:2. MAIN OUTCOME MEASURES: Incidence of maternal near-miss, maternal near-miss to maternal mortality ratio, and cause of and factors associated with maternal near-miss. RESULTS: Out of 8433 live births, 288 maternal near-miss cases and 62 maternal deaths were identified. In all, 454 healthy controls were recruited for comparison. Maternal near-miss and maternal death incidence ratios were 34.2 (95% CI 30.2-38.1) and 7.4 (95% CI 5.5-9.2) per 1000 live births, respectively with a maternal near-miss to mortality ratio of 4.6:1. Cause of near-miss was pre-eclampsia/eclampsia (41.0%), haemorrhage (12.2%), maternal sepsis (11.1%) and ruptured uterus (4.2%). A major factor associated with maternal near-miss was maternal fever within the 7 days before birth (OR 5.95, 95%CI 3.754-9.424). Spontaneous onset of labour was protective against near-miss (OR 0.09 95% CI 0.057-0.141). CONCLUSION: For every maternal death, there were nearly five maternal near-misses. Women having a fever in the 7 days before delivery were six times more likely to experience a near-miss than women not having fever. TWEETABLE ABSTRACT: Maternal near-miss exceeds maternal death by 5:1, with the leading cause of maternal near-miss was pre-eclampsia/eclampsia.

Expected background rates of latent TB infection in London inner city schools: lessons from a TB contact investigation exercise in a secondary school.

Following an extensive contact tracing exercise at a school in a London borough with one of highest tuberculosis (TB) rates in England, we estimated the background prevalence of latent TB infection to be significantly less than the widely accepted 10%. We screened 271 pupils aged 14-15 years in two groups: 96 pupils in group 1 had significant exposure (>8 h/week in the same room) to a case of infectious TB and 175 in group 2 who had minimal exposure. In group 1, 26% were diagnosed with latent or active TB, compared to 6.3% in group 2. Risk factors for TB infection (e.g. previous exposure or link to high-prevalence communities) were analysed using a cohort study design. In the univariable analysis only being in contact group 1 was statistically significantly associated with being a case (OR 5.25, 95%, P < 0.001). In the multivariable model contact group 1 remained significantly associated with being a case (adjusted OR 4.40, P = 0.001). We concluded that the 6.3% yield of TB infection in contact group 2 is either similar to or higher than the background prevalence rate of latent TB infection (LTBI) in this high TB prevalence London borough. Other parts of England with lower TB prevalence are likely to have even lower LTBI rates.

Molecular fingerprinting of complex grass allergoids: size assessments reveal new insights in epitope repertoires and functional capacities.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is a well-documented treatment for allergic disease which involves injections of native allergen or modified (allergoid) extracts. The use of allergoid vaccines is a growing sector of the allergy immunotherapy market, associated with shorter-course therapy. The aim of this study was the structural and immunological characterisation of group 1 (Lol p 1) IgG-binding epitopes within a complex mix grass allergoid formulation containing rye grass. METHODS: HP-SEC was used to resolve a mix grass allergoid preparation of high molecular weight into several distinct fractions with defined molecular weight and elution profiles. Allergen verification of the HP-SEC allergoid fractions was confirmed by mass spectrometry analysis. IgE and IgG immunoreactivity of the allergoid preparations was explored and Lol p 1 specific IgG-binding epitopes mapped by SPOT synthesis technology (PepSpot™) with structural analysis based on a Lol p 1 homology model. RESULTS: Grass specific IgE reactivity of the mix grass modified extract (allergoid) was diminished in comparison with the mix grass native extract. A difference in IgG profiles was observed between an intact mix grass allergoid preparation and HP-SEC allergoid fractions, which indicated enhancement of accessible reactive IgG epitopes across size distribution profiles of the mix grass allergoid formulation. Detailed analysis of the epitope specificity showed retention of six Lol p 1 IgG-binding epitopes in the mix grass modified extract. CONCLUSION: The structural and immunological changes which take place following the grass allergen modification process was further unravelled revealing distinct IgG immunological profiles. All epitopes were mapped on the solvent exposed area of Lol p 1 homology model accessible for IgG binding. One of the epitopes was identified as an 'immunodominant' Lol p 1 IgG-binding epitope (62-IFKDGRGCGSCFEIK-76) and classified as a novel epitope. The results from this study support the concept that modification allows shorter-course therapy options as a result of providing an IgG epitope repertoire important for efficacy. Additionally, the work paves the way to help further develop methods for standardising allergoid platforms.

Choice of tip, signal stability, and practical aspects of piezoresponse-force-microscopy.

Piezoresponse force-microscopy (PFM) has become the standard tool to investigate ferroelectrics on the micro- and nanoscale. However, reliability of PFM signals is often problematic and their quantification is challenging and thus not widely applied. Here, we present a study of the reproducibility of PFM signals and of the so-called PFM background signal which has been reported in the literature. We find that PFM signals are generally reproducible to certain extents. The PFM signal difference between 180° domains on periodically poled lithium niobate (PPLN) is taken as the reference signal in a large number of measurements, carried out in a low frequency regime (30-70 kHz). We show that in comparison to Pt coated tips, diamond coated tips exhibit improved signal stability, lower background signal, and less imaging artifacts related to PFM which is reflected in the spread of measurements. This is attributed to the improved mechanical stability of the conductive layer. The average deviation of the mean PFM signal is 38.3%, for a diamond coated tip. Although this deviation is relatively high, it is far better than values from the literature which showed a deviation of approx. 73.1%. Additionally, we find that the average deviation of the background signal from 0 is 11.6% of the PPLN domain contrast. Thus, the background signal needs to be taken into account when quantifying PFM signals and should be subtracted from PFM signals. Those results are important for quantification of PFM signals, since PPLN might be used for this purpose when PFM signals measured on PPLN are related to its macroscopic d33 coefficient. Finally, the crucial influence of sample polishing on PFM signals is shown and we recommend to use a multistep polishing route with a final step involving 200 nm sized colloidal silica particles.

The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPL®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy.

Infectious disease vaccine potency is affected by antigen adjuvant adsorption. WHO and EMA guidelines recommend limits and experimental monitoring of adsorption in vaccines and allergy immunotherapies. Adsorbed allergoids and MPL® in MATA-MPL allergy immunotherapy formulations effectively treat IgE mitigated allergy. Understanding vaccine antigen adjuvant adsorption allows optimisation of potency and should be seen as good practice; however current understanding is seldom applied to allergy immunotherapies. The allergoid and MPL® adsorption to MCT in MATA-MPL allergy immunotherapy formulations was experimental determination using specific allergen IgE allerginicity and MPL® content methods. Binding forces between MPL® and MCT were investigated by competition binding experiments. MATA-MPL samples with different allergoids gave results within 100-104% of the theoretical 50µg/mL MPL® content. Unmodified drug substance samples showed significant desirable IgE antigenicity, 1040-170 QAU/mL. MATA-MPL supernatant samples with different allergoids gave results of ≤2 µg/mL MPL® and ≤0.1-1.4 QAU/mL IgE antigenicity, demonstrating approximately ≥96 & 99% adsorption respectively. Allergoid and MPL® adsorption in different MATA-MPL allergy immunotherapy formulations is consistent and meets guideline recommendations. MCT formulations treated to disrupt electrostatic, hydrophobic and ligand exchange interactions, gave an MPL® content of ≤2 µg/mL in supernatant samples. MCT formulations treated to disrupt aromatic interactions, gave an MPL® content of 73-92 µg/mL in supernatant samples. MPL® adsorption to l-tyrosine in MCT formulations is based on interactions between the 2-deoxy-2-aminoglucose backbone on MPL® and aromatic ring of l-tyrosine in MCT, such as C-H⋯π interaction. MCT could be an alternative adjuvant depot for some infectious disease antigens.

An open study of antibiotics for the treatment of pre-pouch ileitis following restorative proctocolectomy with ileal pouch-anal anastomosis.

BACKGROUND: Pre-pouch ileitis is a recently described condition which may occur following restorative proctocolectomy. Its aetiology remains unknown and only one study has reported the effect of treatment. We report a series of fourteen patients treated and followed up with repeat pouchoscopy. AIM: To study the effectiveness of antibiotics for the treatment of pre-pouch ileitis following restorative proctocolectomy with ileal pouch-anal anastomosis. METHODS: Fourteen consecutive patients with symptomatic pre-pouch ileitis were treated with ciprofloxacin 500 mg b.d. and metronidazole 400 mg b.d. for 28 days. All had concurrent pouchitis. Symptomatic, endoscopic and histological assessment was performed before and following treatment using the pouchitis disease activity index (PDAI). Symptomatic remission was defined as a score of 0 in the clinical component of the PDAI. RESULTS: Twelve (86%) patients experienced symptomatic remission. Stool frequency fell from a median of 12 (range 8-20) to 6 (4-17) (P = 0.002). There was a significant reduction in the anatomical length of pre-pouch ileitis with nine (64%) patients having either a resolution or a reduction in length of pre-pouch ileitis from a median of 10 cm (range 3-20 cm) to a median of 1 cm (range 0-10 cm) (P = 0.007). CONCLUSION: Combination antibiotic therapy in this uncontrolled study appears effective in reducing the length of pre-pouch ileitis and in inducing symptomatic remission in most patients whether or not its extent is reduced.

Electron backscatter diffraction as a domain analysis technique in BiFeO(3)-PbTiO(3) single crystals.

xBiFeO(3)-(1-x)PbTiO(3) single crystals were grown via a flux method for a range of compositions. Presented here is a study of the domain configuration in the 0.5BiFeO(3)-0.5PbTiO(3) composition using electron backscatter diffraction to demonstrate the ability of the technique to map ferroelastic domain structures at the micron and submicron scale. The micron-scale domains exhibit an angle of approximately 85 degrees between each variant, indicative of a ferroelastic domain wall in a tetragonal system with a spontaneous strain, c/a - 1 of 0.10, in excellent agreement with the lattice parameters derived from x-ray diffraction. Contrast seen in forescatter images is attributed to variations in the direction of the electrical polarization vector, providing images of ferroelectric domain patterns.

Pre-pouch ileitis: a disease of the ileum in ulcerative colitis after restorative proctocolectomy.

OBJECTIVE: Ileal inflammation in ulcerative colitis can occur as backwash ileitis or prestomal ileitis. After restorative proctocolectomy (RPC), ileal inflammation may be present in the pouch (pouchitis) but inflammation proximal to the pouch in the neo-terminal ileum, so called pre-pouch ileitis (PI), has also been observed. As pouchitis is increasingly common and PI can mimic it, our aim was to characterize this condition. SUBJECTS AND METHODS: A review of prospectively collected data on 571 inflammatory bowel disease patients undergoing follow-up after RPC in a single centre over 22 years was performed. The histology of biopsy material was reviewed and staining for colonic mucosal phenotypic changes was undertaken. It was not routine practice to prospectively assess all patients for pre-pouch ileitis when the database was constructed. RESULTS: Of 19 patients with inflammation of the pre-pouch neo-terminal ileum (NTI) identified three had Crohn's disease and one a NSAID stricture. The remaining 15 had a characteristic diffuse inflammation extending from the NTI-pouch junction proximally: pre-pouch ileitis. The inflammation extended proximally for up to 50 cm. Fistula formation was seen in only one. Seven (47%) of 15 had pouchitis but only two had suffered backwash ileitis pre-operatively. Seven responded to medical therapy and four to surgery. The histological appearances including staining for colonic phenotypic change were similar in PI and pouchitis. CONCLUSION: Pre-pouch ileitis is uncommon. As the patients' previous diagnosis of UC was confirmed and there was no radiological or histological evidence of Crohn's disease, PI appears to have a distinct pathogenesis from Crohn's disease.

Fragmentations and reactions of the organophosphate insecticide Diazinon and its oxygen analog Diazoxon studied by electrospray ionization ion trap mass spectrometry.

The fragmentations and reactions of Diazinon and related compounds have been studied by electrospray ionization ion trap mass spectrometry. Several novel fragmentation and rearrangements have been observed, including an intramolecular thiono-thiolo rearrangement. The stability, in the gas-phase, of the protomers of 2-isopropyl-4-methyl-6-pyrimidinol has been demonstrated. The complexity of the gas phase ion processes observed suggest that, at present, caution should be exercised in using this approach for the analysis of environmental and other samples until our understanding of these processes increases considerably.

Human lymphocyte stimulation with pouchitis flora is greater than with flora from a healthy pouch but is suppressed by metronidazole.

BACKGROUND/AIMS: The gut flora may play an important role in the pathogenesis of inflammatory bowel disease. An ileal reservoir or pouch can be created to replace the excised rectum after proctocolectomy. In patients with ulcerative colitis this is subject to inflammation and termed pouchitis. Using bacteria from patients the authors sought evidence for the presence rather than the identity of a pathogenic species in pouchitis, and for its absence in healthy pouches by the differential effect on lymphocyte proliferation. METHODS: An ex vivo cell culture assay was used in which peripheral blood mononuclear cells or lamina propria mononuclear cells were cultured with sterile sonicates of gut flora from patients with or without pouchitis in the presence of antigen presenting cells. RESULTS: Sonicated pouchitis flora produced a consistent and intense proliferation of the mononuclear cells but that produced by sonicates from healthy pouches was minimal (p = 0.012 or 0.018, peripheral blood or lamina propria mononuclear cells). Preparation of the sonicates with the antibiotic metronidazole abolished their stimulatory ability (p = 0.005, peripheral blood mononuclear cells). In separate assays neither direct addition of metronidazole nor of its hydroxy metabolite affected the mononuclear cells' proliferation with alternative stimuli. CONCLUSIONS: These results strongly support a bacterial aetiology for pouchitis.

Fragmentation and reactions of two isomeric O-alkyl S-(2-dialkylamino)ethyl methylphosphonothiolates studied by electrospray ionization/ion trap mass spectrometry.

An initial investigation into the electrospray ionization ion trap mass spectrometry (ESI/ITMS) of simple organophosphorus compounds [1] demonstrated that detailed structural information could be obtained by sequential fragmentation of the ions using collision induced dissociation (CID). Several novel fragmentations/rearrangements were observed and it was apparent that the full potential of this approach could not be exploited until a more detailed understanding of the ion fragmentations was obtained. Such an understanding will only result from a detailed study of a wide range of compounds. The present paper describes the investigation of two isomeric organophosphates of particular relevance to chemical warfare convention (CWC) considerations.

Interactions between HMG boxes.

Many proteins consist of subdomains that can fold and function independently. We investigate here the interaction between the two high mobility group (HMG) box subdomains of the nuclear protein rHMG1. An HMG box is a conserved amino acid sequence of approximately 80 amino acids rich in basic, aromatic and proline side chains that is active in binding DNA in a sequence or structure-specific manner. In the case of HMG1, each box can bind structural DNA substrates including four-way junctions (4WJs) and branched or kinked DNA duplexes. Since proteins containing up to six HMG boxes are known, the question arises whether linking subdomains together influences the folding or function of individual boxes. In an effort to understand interactions between individual DNA-binding domains in HMG1, we created new fusion proteins: one is an inversion of the order of the AB di-domain in HMG1 (BA); in the second, we added a third A domain C-terminal to the AB di-domain (ABA). Pairs of boxes, AB or BA, behave similarly and are functionally active. By contrast, the ABA triple subdomain construct is partially unfolded and is less active than individual boxes or di-domains. Thus, long-range inter-domain effects can influence the activity of HMG boxes.

Stabilization of alpha-helix structure by polar side-chain interactions: complex salt bridges, cation-pi interactions, and C-H em leader O H-bonds.

It is generally understood that helical proteins are stabilized by a combination of hydrophobic and packing interactions, together with H-bonds and electrostatic interactions. Here we show that polar side-chain interactions on the surface can play an important role in helix formation and stability. We review studies on model helical peptides that reveal the effect of weak interactions between side chains on helix stability, focusing on some nonclassical side-chain-side-chain interactions: complex salt bridges, cation-pi, and C-H em leader O H-bonding interactions. Each of these can be shown to contribute to helix stability, and thus must be included in a comprehensive catalogue of helix stabilizing effects. The issue of the structure of the unfolded states of helical peptides is also discussed, in the light of recent experiments showing that these contain substantial amounts of polyproline II conformation.

Characteristics and outcomes of older patients presenting to the emergency department after a fall: a retrospective analysis.

OBJECTIVES: To study older patients presenting to the emergency department after a fall--factors associated with the fall, injuries sustained and outcome. DESIGN: A retrospective analysis using the Emergency Department Information System (EDIS), the Trauma Registry and the patient information database (CCIS), in addition to the patient's emergency and inpatient medical records. SETTING: Emergency department of a major inner city teaching hospital, 1 June-30 November 1997. PATIENTS: All patients over 65 years presenting to the emergency department (ED) after a fall, for whom complete medical records were available. RESULTS: Of 803 patients over 65 years presenting to the ED after a fall, complete records were available for 733 (91.3%) (283 men and 450 women). Extrinsic (accidental) causes were implicated in more than a third of falls (313 patients [42.7%]). A high proportion of the patients were living at home (520; 70.9%) and walking unaided (389; 53.1%). Although absolute numbers of women increased with age, men were as likely as women to present after a fall. Many patients had fallen before--39% of the men (111/283) and 24% of the women (110/450). In 78 patients (10.6%), alcohol misuse may have been a direct cause of the fall. The overall injury rate was 70.5% (517/733 patients), the most common injury being an isolated fracture (269/517 patients; 52.0%). In all, 419 patients (57.2%) were admitted to hospital, 48% (200/419) with a fracture and 52% (219/419) for investigation of the medical cause of the fall. The median length of hospital stay was 6 days (mean, 10.4 days; range, 1-129 days); 35% (146/419) of patients were in hospital for more than 10 days. CONCLUSION: Older patients presenting to the ED after a fall had high injury rates, high admission rates and often prolonged hospitalisation. About a third had fallen before. Patients at risk can be identified in the ED and referred to falls prevention programs.