Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis : protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy

Introduction: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. Methods and analysis: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. Ethics and dissemination: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. Trial registration number: ISRCTN23947730

A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders,  = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen

Transforming access to care for serious mental disorders in slums (the TRANSFORM Project) : rationale, design and protocol

This paper introduces the TRANSFORM project, which aims to improve access to mental health services for people with serious and enduring mental disorders (SMDs – psychotic disorders and severe mood disorders, often with co-occurring substance misuse) living in urban slums in Dhaka (Bangladesh) and Ibadan (Nigeria). People living in slum communities have high rates of SMDs, limited access to mental health services and conditions of chronic hardship. Help is commonly sought from faith-based and traditional healers, but people with SMDs require medical treatment, support and follow-up. This multicentre, international mental health mixed-methods research project will (a) conduct community-based ethnographic assessment using participatory methods to explore community understandings of SMDs and help-seeking; (b) explore the role of traditional and faith-based healing for SMDs, from the perspectives of people with SMDs, caregivers, community members, healers, community health workers (CHWs) and health professionals; (c) co-design, with CHWs and healers, training packages for screening, early detection and referral to mental health services; and (d) implement and evaluate the training packages for clinical and cost-effectiveness in improving access to treatment for those with SMDs. TRANSFORM will develop and test a sustainable intervention that can be integrated into existing clinical care and inform priorities for healthcare providers and policy makers

Effect of managed transition on mental health outcomes for young people at the child–adult mental health service boundary : a randomised clinical trial

Background: Poor transition planning contributes to discontinuity of care at the child–adult mental health service boundary (SB), adversely affecting mental health outcomes in young people (YP). The aim of the study was to determine whether managed transition (MT) improves mental health outcomes of YP reaching the child/adolescent mental health service (CAMHS) boundary compared with usual care (UC). Methods: A two-arm cluster-randomised trial (ISRCTN83240263 and NCT03013595) with clusters allocated 1:2 between MT and UC. Recruitment took place in 40 CAMHS (eight European countries) between October 2015 and December 2016. Eligible participants were CAMHS service users who were receiving treatment or had a diagnosed mental disorder, had an IQ ⩾ 70 and were within 1 year of reaching the SB. MT was a multi-component intervention that included CAMHS training, systematic identification of YP approaching SB, a structured assessment (Transition Readiness and Appropriateness Measure) and sharing of information between CAMHS and adult mental health services. The primary outcome was HoNOSCA (Health of the Nation Outcome Scale for Children and Adolescents) score 15-months post-entry to the trial. Results: The mean difference in HoNOSCA scores between the MT and UC arms at 15 months was −1.11 points (95% confidence interval −2.07 to −0.14, p = 0.03). The cost of delivering the intervention was relatively modest (€17–€65 per service user). Conclusions: MT led to improved mental health of YP after the SB but the magnitude of the effect was small. The intervention can be implemented at low cost and form part of planned and purposeful transitional care

Hodgkin disease (1973-2002) : long-term survival and cure fractions.

The Nottinghamshire Lymphoma Registry contains the details of all patients diagnosed with lymphoma (since 1 January 1973) within a defined geographical area with a stable population of 1.1 million. The aim of this study was to investigate the relative survival and estimate the cure fraction for patients with Hodgkin disease (HD) using various cure fraction models. Five- and 10-year survival was estimated in comparison to the general population of the same age, gender and year of diagnosis. Relative survival probabilities at 10 years were 52.3% for the 1973-1982 cohort, 67.8% (1983-1992) and 75.7% (1993-2002). The estimated cured fraction (π) was 45%, 65% and 75%, respectively, for the same cohorts. There was very little excess mortality after 4 years from treatment. The prognosis of patients with HD has improved progressively within a defined unselected population over this 30-year period. In the 1993-2002 cohort the prognosis after 4 years of treatment is almost the same as for a normal population

Visual impairment registration : evaluation of agreement among ophthalmologists

Purpose: To evaluate consistency among consultant ophthalmologists in registration of visual impairment of patients with glaucoma who had a significant visual field component to their visual loss. Method: Thirty UK NHS consultant ophthalmologists were asked to grade data sets comprising both visual acuity and visual fields as severely sight impaired, partially sight impaired, or neither. To assess intra-consultant agreement, a group of graders agreed to repeat the process. Results: Kappa for inter-consultant agreement (n=30) for meeting the eligibility criteria for visual impairment registration was 0.232 (95% CI 0.142–0.345), the corresponding inter-class correlation score was 0.2 (95% CI 0.172 to 0.344). Kappa for intra-consultant agreement (n=16) ranged from 0.007 to 0.9118. Conclusions: When presented with the clinical data necessary to decide whether patients with severe visual field loss are eligible for vision impairment registration, there is very poor intra- and inter-observer agreement among consultant ophthalmologists with regard to eligibility. The poor agreement indicates that these criteria are open to significant subjective interpretation that may be a source of either under- or over-registration of visual impairment in this group of patients in the UK. This inconsistency will affect the access of visually impaired glaucoma patients to support services and may result in inaccurate recording of the prevalence of registerable visual disability among glaucoma patients with severe visual field loss. More objective criteria with less potential for misclassification should be introduced

Epidemiology and outcome of fracture of the hip in women aged 65 years and under : a cohort study

We examined prospectively collected data from 6782 consecutive hip fractures and identified 327 fractures in 315 women aged ≤65 years. We report on their demographic characteristics, treatment and outcome and compare them with a cohort of 4810 hip fractures in 4542 women aged > 65 years. The first significant increase in age-related incidence of hip fracture was at 45, rather than 50, which is when screening by the osteoporosis service starts in most health areas. Hip fractures in younger women are sustained by a population at risk as a result of underlying disease. Mortality of younger women with hip fracture was 46 times the background mortality of the female population. Smoking had a strong influence on the relative risk of 'early' (≤ 65 years of age) fracture. Lag screw fixation was the most common method of operative treatment. General complication rates were low, as were re-operation rates for cemented prostheses. Kaplan-Meier implant survivorship of displaced intracapsular fractures treated by reduction and lag screw fixation was 71% (95% confidence interval 56 to 81) at five years. The best form of treatment remains controversial

Development and external validation of a nomogram and online tool to predict bowel dysfunction following restorative rectal cancer resection : the POLARS score

Bowel dysfunction is common following a restorative rectal cancer resection, but symptom severity and the degree of quality of life impairment is highly variable. An internationally validated patient-reported outcome measure, Low Anterior Resection Syndrome (LARS) score, now enables these symptoms to be measured. The study purpose was: (1) to develop a model that predicts postoperative bowel function; (2) externally validate the model and (3) incorporate these findings into a nomogram and online tool in order to individualise patient counselling and aid preoperative consent

Concesión de viático a don Mathias Concanon, sacerdote irlandés

Fecha del documento: 1745-02-26. 4 páginasMemorial de don Mathias Concanon, presbítero irlandés y colegial en el de San Jorge de Alcalá de Henares, que ha acabado sus siete años de estuduos y se halla hábil y capaz para predicar el Evangelio a los fieles ocultos de Irlanda, para lo que solicita la ayuda de costa que se acostumbra. El marqués de la Ensenada remite el memorial a Jaime Antonio Fevre, que juzga propio de la real piedad del rey que le conceda la ayuda de costa que solicita. Respuesta final: "Como dice el Padre Confesor".Proyecto Proyección Política y Social de la Comunidad Irlandesa en la Monarquía hispánica y en la América Colonial de la Edad Moderna(siglos XVI-XVIII) (HAR2009-11339 - subprograma HIST) del Ministerio de Economía y Competitividad en colaboración con el Consejo Superior de Investigaciones Científicas (CSIC), Embajada de Irlanda en Madrid, National University of Ireland (NUI) Maynooth, University College Dublin y Trinity College DublinMathias ConcanonFelipe VColegio de San Jorge de la Univ. Alcalá HenaresSí100 ducadosSíN