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1.
P Howlett A Walder D Lisk A N&#x;jai M Lado C Brown S Sevalie F R Sesay M G Semple J T Scott 《Lancet》2017
Background
Neurological and psychiatric sequelae in survivors of Ebola virus disease have been noted in previous epidemics, but few details have been documented. One case-report reported abnormal CT brain findings in one survivor. We aimed to document full neurological history and clinical examination findings, psychiatric screening, and the need for brain imaging in people who survived Ebola virus disease.Methods
Adults (>16 years) in Sierra Leone who had survived Ebola virus disease with defined criteria of confirmed disease and one major or two minor symptoms were invited to attend clinic. Patients underwent full history, neurological examination, and psychiatric screening. Patients were referred, as necessary, to a tertiary neurology and psychiatric clinic, where brain CT scans were requested.Findings
87 (25%) of 354 patients in the initial cohort fitted the defined criteria. 38 of 45 patients who were contactable attended our screening clinic (24 women [63%], median age 34 years [IQR 25–43]). Median length of initial stay in hospital during Ebola virus disease was 21 days (13–28) and median time to our screening clinic post discharge was 431 days (402–497). 17 (45%) of the 38 clinic attenders reported loss of consciousness and seven (18%) reported seizures during their acute phase. In the screening clinic, 14 (50%) of 28 patients with headache reported eye symptoms (eye pain, itching, redness, blurred vision, or altered vision), seven (25%) photophobia, six (21%) intermittent fevers, five (18%) dizziness or vertigo, two (7%) tinnitus, and two (7%) scotoma. Headaches were usually intermittent and localised as frontal, unilateral, or band-like. 23 (61%) of the clinic attenders were offered referral to a tertiary neurological and psychiatric clinic, and 17 (42%) required CT brain scanning. At the screening clinic, psychiatric symptoms included insomnia (21/38, 55%), depression (12/38, 32%), and anxiety (11/38, 29%).Interpretation
A broad range of important neurological and psychiatric sequelae were present in our selected group of Ebola virus disease survivors over a year after initial discharge. Intermittent headaches, associated with photophobia, intermittent fever, and dizziness or vertigo, were the most frequent neurological features. Common psychiatric symptoms included insomnia, depression, and anxiety. Our experience suggests that there is a need for tertiary level neurological and psychiatric clinics.Funding
JTS is supported by the Wellcome Trust. MGS is supported by the UK National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections. This project is supported by the Enhancing Research Activity in Epidemic Situations. 相似文献2.
Yael Hacohen Kshitij Mankad W Kling Chong Frederik Barkhof Angela Vincent Ming Lim Evangeline Wassmer Olga Ciccarelli Cheryl Hemingway 《Lancet》2017
Background
Paediatric relapsing demyelinating syndromes of the CNS define a group of diseases that have different phenotypes. Although for some of them, such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD), diagnostic criteria have been developed, diagnostic uncertainties are not uncommon. We aimed to identify the key features that unify phenotypes, and focused on patients with myelin oligodendrocyte glycoprotein (MOG) antibodies, to investigate whether they show distinctive clinical and radiological features, independently of their original diagnosis. We then generated a diagnostic algorithm for clinical use.Methods
We reviewed the clinical characteristics, MOG and AQP4 antibodies, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with relapsing demyelinating syndromes. A neuroradiologist, masked to the diagnosis, scored the MRI scans. Clinical, radiological, and serological test results were compared between the different relapsing demyelinating syndromes.Findings
62 children (56%) were diagnosed with multiple sclerosis, 27 (25%) with NMOSD, 14 (13%) with multiphasic disseminated encephalomyelitis (MDEM), and 7 (6%) with relapsing idiopathic optic neuritis (RION). Paediatric multiple sclerosis and NMOSD with AQP4 antibodies showed radiological and serological features typical of the respective adult phenotypes. Eight children with NMOSD (30%) were positive for AQP4 antibodies. MOG antibodies were found in 16 (83%) of 19 NMOSD patients without AQP4 antibodies, in all 14 children with MDEM, and in two with RION (33%). Children with MOG antibodies were younger, less likely to present with area postrema syndrome, had lower disability, longer time to relapse, and more cerebellar peduncle lesions than those with AQP4 antibody-positive NMOSD (all p<0·05). A diagnostic algorithm, applicable to any episode of CNS demyelination, led to four main relapsing demyelinating syndromes: multiple sclerosis, NMOSD with APQ4 antibodies, MOG-antibody-associated disease, and antibody-negative relapsing demyelinating syndrome.Interpretation
Using an integrative approach of clinical phenotyping, radiological analysis, and MOG and AQP4 antibodies, we were able to delineate patients to different disease phenotypes—namely, multiple sclerosis, MOG antibody spectrum disorder, and AQP4 antibody spectrum disorder. Although the clinical presentation can overlap (eg, optic neuritis and transverse myelitis) the pathogenic mechanisms are likely to be different. A correct diagnosis in children with non-multiple sclerosis phenotypes has both treatment and prognostic implications.Funding
National Institute for Health Research. 相似文献3.
Background
Reporting of the incidence of child maltreatment by parents and children might differ with implications for optimum research methodologies to determine the incidence of maltreatment. Our aim was to compare parent and child reports of child maltreatment in mainland China.Methods
A cross-sectional study was done in two primary schools and two secondary schools in urban and rural Zhejiang Province. Children aged 10–16 years and their parents completed a questionnaire survey. The same questions about child maltreatment appeared in both parent and child questionnaires and included 38 disciplinary acts (21 physical, 12 emotional, and five, non-contact). Parent–child pairs from the same household were matched to compare parent–child reports of maltreatment. We used McNemar's χ2 test and Cohen's kappa coefficient for the statistical analysis. The study was approved by University College London and Zhejiang University Research Ethics Committees. All participants gave informed consent.Findings
Questionnaires were completed by 611 parents and 821 children, with 324 mother–child pairs and 235 father–child pairs. For mother–child pairs, the lifetime prevalences of maltreatment (mothers vs their children) were 53·4% versus 36·7% for physical acts; 76·2% versus 50·0% for emotional acts; and 19·4% versus 13·0% for non-contact acts. For father–child pairs, the lifetime prevalences of maltreatment (fathers vs their children) were 57·9% versus 39·0% for physical acts; 71·5% versus 44·3% for emotional acts; and 22·6% versus 16·2% for non-contact acts. The prevalence of emotional maltreatment in the previous year was reported more by parents than children (55·9% mothers vs 32·7% children; 54·0% fathers vs 31·5% children), with no differences for physical maltreatment and non-contact punishment. The Cohen's kappa coefficients ranged from 0·09 to 0·39, indicating low agreement between parent–child reports.Interpretation
High levels of child maltreatment are common in China. To gain accurate figures for maltreatment, both children and caregivers should be considered in research. Consistently lower figures in children might relate to recall bias or acceptance of acts of maltreatment as normal. Parents readily admit maltreating their children, possibly indicating its normalisation in China, indicating the need for parenting education.Funding
China Scholarship Council and Universities' China Committee in London. 相似文献4.
Background
Trachoma is the most common infectious cause of blindness worldwide. In-vivo confocal microscopy (IVCM) provides high-resolution images of the ocular surface. We have previously reported a grading system for the quantitative assessment of these images in scarring trachoma. We found that the presence of trachomatous scarring was strongly associated with the presence of dendritiform cells (DFCs). The present study assessed whether there is an association between DFCs and clinical progression in scarring.Methods
Participants with trachomatous scarring in northern Tanzania were examined at baseline and 24 months (clinical assessment, photography, and IVCM of the upper tarsal conjunctiva). IVCM images were graded according to a validated grading system. Two independent observers identified scarring progression by comparing photographs taken at baseline and 24 months.Findings
800 participants were assessed clinically at baseline and 617 of them were re-examined at 24 months. There were 465 individuals who had photographs that could be confidently graded as having either progression or scarring, or not having progression. Progression was found to occur in 113 (24%) of the 465 individuals. IVCM images were obtained in 344 of these participants at baseline and 24 months, and 29 (8·4%) had DFCs present at baseline. The presence of DFCs at baseline was significantly associated with scarring progression (p=0·01), including adjustment for age and sex (p=0·03).Interpretation
The presence of DFCs on IVCM images is associated with progressive trachomatous conjunctival scarring. DFCs are thought to represent dendritic cells, which have a central role in mediating the immune response and potentially in the pathogenesis of trachomatous scarring. The nature of these cells warrants further investigation, potentially as a novel antifibrotic therapeutic target.Funding
Wellcome Trust senior research fellowship (to MB). National Institute for Health and Research academic clinical fellowship (to JH). 相似文献5.
Background
Infections can trigger acute vascular events but the differential effect of specific respiratory pathogens is unknown. We aimed to quantify the association between laboratory-confirmed respiratory bacterial or viral infections and first myocardial infarction or stroke to inform intervention development and targeting.Methods
Scottish Morbidity Record data on first myocardial infarction or stroke (International Classification of Diseases, 10th revision, codes) were linked to records of Streptococcus pneumoniae, influenza, rhinovirus, parainfluenza, respiratory syncytial virus, or human metapneumovirus from the Electronic Communication of Surveillance in Scotland (National Services Scotland) dataset on individuals aged 40 years or older from Jan 1, 2004, to Dec 31, 2014. We analysed incidence ratios for myocardial infarction or stroke in the 28 days after infection compared with baseline using self-controlled case series.Findings
There were 1227 individuals with myocardial infarction (751 men [61%]) and 762 with stroke (392 men [51%]). Median age was 68 years (IQR 59–77). The relative incidence of myocardial infarction was markedly raised in the first 1–3 days after both bacterial and viral infections (incidence ratio 5·98, 95% CI 2·47–14·4 [p<0·0001] and 5·59, 1·77–17·6 [p=0·003], respectively) and persisted for about 1 week. For stroke, the respective relative incidence after respiratory infection was even higher for days 1–3 (12·3, 5·48–27·7 [p<0·0001] and 6·79, 1·67–27·50 [p=0·007]). Elevated stroke risks after both bacterial and viral infections persisted to 28 days (p<0·0001).Interpretation
Our findings suggest that respiratory bacterial and viral infections act as vascular triggers. For stroke, the incidence ratio remained elevated a month after the date of respiratory sampling but for myocardial infarction the raised incidence ratio appeared to be more transient, suggesting potentially different mechanisms. This study highlights the need to ensure adequate uptake of influenza and pneumococcal vaccines as well as appropriate treatment during infections to reduce vascular risk.Funding
Academy of Medical Sciences. 相似文献6.
Background
Neuroblastoma is the commonest cancer in infants. Survival in high-risk groups is low (40–50%). Newer treatments are needed to improve survival and morbidity. Cytomegalovirus (CMV) is a common viral infection, which increases γδ T cells. We investigated the use of CMV-reactive γδ T cells as a potential new immunotherapy.Methods
Peripheral blood mononuclear cells from 30 paediatric haemato-oncology patients with or without CMV infection were analysed by flow cytometry. γδ T cells were expanded, and then co-cultured with CMV targets or neuroblastoma cells. T-cell activation, cytokine secretion, killing activity, and mechanisms were determined by ELISA, MTT colorimetric assay, and blocking assays. Novel γδ T cell receptors (TCR) were identified by sequencing.Findings
In paediatric haemato-oncology patients, acute CMV led to higher proportions of total γδ T cells (p=0·0002) with the dominant subtype Vδ1 (p=0·0035). CMV-reactive γδ T cells were of the effector memory phenotype and expanded to clinically significant numbers for adoptive transfer. When compared with γδ T cells from CMV-negative patients, CMV-reactive γδ T cells had statistically significantly higher interferon γ release (p<0·001) in co-cultures with CMV-infected fibroblasts and showed cytolytic activity against CMV-infected fibroblasts and neuroblastoma cells which was mediated by γδ TCR and the NKG2D receptor. Sequencing showed that the dominant γδ T-cell chains in CMV-infected patients were Vδ1 Vγ2. Within the TCRs, CDR3 sequences had minimal diversity, γ chains had wide variations, and we identified a novel subpopulation in some patients.Interpretation
We show that acute CMV infection in paediatric haemato-oncology patients leads to an increase in the Vδ1 Vγ2 subtype of γδ T cells. They can be expanded for adoptive transfer and are likely to retain killing ability post expansion. They recognise and kill CMV-infected targets and neuroblastoma cells via the γδ TCR and the NKG2D receptor. We have identified a novel TCR in a subpopulation of CMV-positive patients.Funding
Great Ormond Street Charity, National Institute for Health Research Biomedical Research Centre, Olivia Hodson Cancer Fund. 相似文献7.
Sunil Bhopal Deepali Verma Gauri Divan Zelee Hill Jane Barlow Reetabrata Roy Betty Kirkwood 《Lancet》2017
Background
SPRING-ELS (Early Life Stress) is a substudy of the SPRING cluster randomised controlled trial that is assessing a home visits programme in rural India promoting early child development and growth. Early life stress interferes with healthy child development so our aim was to evaluate its role in the SPRING causal pathway. We report findings from the preparatory phase of SPRING-ELS.Methods
To develop an explanatory model of early life stress in the community, 45 mothers of children under 2 years old took part in eight focus group discussions. To determine potential barriers to sampling, in-depth interviews were done with five mothers and two barbers (to understand cultural beliefs about young children's hair). In addition, five focus group discussions were done with mothers, grandmothers, and barbers. Salivary and hair cortisol (to assess diurnal rhythm and chronic stress) were measured in 13 children aged 11–13 months. The SPRING trial is registered with ClinicalTrials.gov, number NCT02059863.Findings
Causes of stress included violence, poverty, poor hygiene, neglect and poor care, maternal stress, and carer alcoholism. Consequences included a range of physical and mental adversity. Improved caregiving was seen as the most important prevention method. However, in contrast to previous research, stress was seen to affect older children, who have a better understanding of their environment, than younger infants. Taking saliva samples was straightforward. Mothers preferred to be helped by assessors to take these samples rather than doing it themselves. However, hair sampling was challenging. There are many cultural beliefs surrounding young children's hair and a child's first haircut is a ceremonial occasion: rates of refusal were high (four of 13 families refused). Sample size was adjusted accordingly.Interpretation
Measuring early life stress in the community is feasible and acceptable. Careful introduction in the community has achieved a 14% refusal rate to take hair samples despite major cultural barriers. These stress measures have been integrated into SPRING outcome assessments, which are being performed with a total of 1200 children. Each assessment is done over 2 days when a child reaches 1 year of age. 60 children are being assessed at home each week using salivary and hair cortisol measurments and questionnaires of environmental stressors developed using findings from our explanatory model. To our knowledge, SPRING is the first large child health intervention trial to include measures of early life stress and the first time that hair cortisol will be assessed in South Asian children.Funding
Wellcome Trust research training fellowship to SB (grant number 107818/Z/15/Z). 相似文献8.
Background
Greater investment in primary care yields better population health outcomes. However, in the past decade general practice (GP) funding has reduced, while general practitioner workload has risen and secondary care funding has increased. To date, the impact of broader aspects of GP funding has not been examined. Using newly released GP financial data, we aimed to explore the association between greater investment in primary care and secondary care usage and costs applied at a national level in England.Methods
We constructed linear regression models to explore the association between practice funding for essential services and quality and outcomes framework (QOF) achievement, secondary care usage (accident and emergency [A&E] attendance, emergency admission, and outpatient attendance rates per 1000 registered patients), and patient satisfaction, adjusted for practice and demographic variables. We then conducted financial modelling to predict the impact of a hypothetical 10% funding increase on secondary care costs, for which we used standard cost estimates.Findings
We analysed 7767 practices in England. Mean funding per patient was £79·81 (95% CI 67·01–100·67). Funding was lower in General Medical Services (GMS) practices, which hold national contracts, than in Personal Medical Services practices, which have local contracts (£76·00 [66·52–89·20] vs 84·43 [66·68–107·09]). In GMS practices, greater funding was significantly associated with lower emergency admissions (regression coefficient β=–0·22), lower A&E attendances (?1·04), and higher patient satisfaction (overall satisfaction 0·4). We found no significant association with outpatient attendance or QOF performance. In our financial model, a 10% increase in primary care funding would create a return on investment of 78% in GMS practices overall and up to 110% in GMS practices receiving funding above the national capitation formula.Interpretation
GMS practices with higher levels of funding had lower secondary care usage and higher patient satisfaction. The lack of association between funding and QOF achievement might be attributable to the different funding stream and incentives for QOF. Our findings support the case for greater investment in primary care where the value of investment is over and above the national capitation formula.Funding
National Institute for Health Research. 相似文献9.
Jason J Ong Haochu Li Wu Dan Hongyun Fu Ewen Liu Wei Ma Demin Kang Meizhen Liao Gifty Marley Chongyi Wei Weiming Tang Stephen Pan Chuncheng Liu Bin Yang Ligang Yang Shujie Huang Joseph D Tucker 《Lancet》2017
Background
The wide range of interventions to promote HIV testing might inadvertently contribute to coerced testing. There has been concern about coerced HIV self-testing in non-research settings where there is minimal supervision. The aim of this study was to examine the prevalence and correlates of coerced HIV testing among men who have sex with men (MSM) in China.Methods
In July 2016, we recruited MSM from eight cities through BlueD, a gay social network mobile application. Data on sociodemographics, HIV self-testing, HIV facility testing, test coercion, condomless sex in the past 3 months, and transactional sex were collected. Coerced testing was defined as someone (partner, friend, employer, or others) forcing the participant to take an HIV test. Multivariable logistic regression was used to examine correlates of coerced testing among MSM who had ever received HIV testing.Findings
1312 men were included, most of whom were young (mean age 26·9 years [SD 6·3]). 1002 (76%) men were identified as gay, and 685 (52%) men had used HIV self-testing. 64 (15%) men reported coerced testing, and 39 of these men were forced to have a self-test. Adjusting for age, education, income, and residence, men who reported coerced testing were more likely to have ever self-tested for HIV (adjusted odds ratio 4·25; 95% CI 2·23–8·09). Coerced testing was more common among men who had sex with casual partners in exchange for gifts or money (3·34; 1·90–5·86) than among men who did not report transactional sex. Coerced testing was also more common among MSM who reported condomless anal sex in the preceding 3 months (2·38; 1·43–3·98) than among men who did not report condomless anal sex.Interpretation
HIV test coercion is uncommon among MSM in China, but is more likely in men who used HIV self-tests. As HIV self-testing is scaled up worldwide, research and enhanced post-test surveillance are needed.Funding
National Institute of Allergy and Infectious Diseases (1R01AI114310-01) and the Australian National Health Medical Research Council (APP1104781). The funders had no role in the design of the study, the collection, analysis, and interpretation of data, or in the writing of the Abstract. 相似文献10.
Background
Cancer cell plasticity, as seen in epithelial-to-mesenchymal transition, can lead to metastasis and therapeutic failure. Another cell type, the amoeboid, has now been isolated in oral cancer. Previously seen in, but not isolated from melanomas and sarcomas, it has been associated with poorer prognosis. The aim of the study was to investigate the role of the amoeboid cell in oral cancer, with the hypothesis that it is a plastic, but more invasive and chemoresistant, cell type.Methods
In this in-vitro study of oral cancer cell lines (n=6), fresh tumour specimens, and mice, we used high-throughput invasion assays, migration and drug response assays, protein and gene expression profiling, mechanistic and pathway analysis, fluorescence-activated cell sorting, gene knockdowns, and immunostaining. At least three cell lines were used for each laboratory technique, with a minimum of triplicate repeats and appropriate statistical analysis.Findings
In all cell lines, amoeboid cells were smaller than both epithelial and mesenchymal cells (median cell area 295 μm2 [IQR 218–399] vs 884 [573–1281] vs 598 [413–815]) but were significantly more migratory with a mean velocity of 1·1 μm/min (SD 0·2) versus 0·16 (0·08) for mesenchymal cells (p<0·0001). Amoeboid cells were four to 20 times more invasive than other cell types (p<0·0001). Greater chemoresistance was demonstrated against common agents including paclitaxel and etoposide. Gene analysis produced signatures associated with angiogenesis, anti-apoptosis, and invasion. Stemness genes were upregulated. Plasticity between phenotypes was clearly seen.Interpretation
We describe a new amoeboid cell phenotype, which is derived from epithelial cancer cells, that might confer upon carcinomas a greater ability to invade, disseminate, and resist therapy. A switch to an amoeboid phenotype could be a useful escape strategy for cancers, providing them with alternative modes for migration and invasion. However, this cell type essentially lacks keratin, which could complicate histopathological assessment of tumour spread. Pathway elucidation might yield new potential amoeboid targets. Targeting amoeboid cells, which may now become possible with their isolation and analysis, could be essential to improve patient outcomes.Funding
Royal College of Surgeons of England, British Association of Oral and Maxillofacial Surgeons, Facial Surgery Research Foundation, Faculty of Dental Surgeons (Royal College of Surgeons of England). 相似文献11.
Satyen Gohil Solange Paredes-Moscosso Micaela Harrasser Andrew Davidoff Martin Pule Marco Della Peruta Amit Nathwani 《Lancet》2017
Background
Immunotherapy with chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers (BiTEs) has shown impressive efficacy against CD19+ malignancies, but translation to other tumour targets is not possible. In this regard, receptor tyrosine kinase like orphan receptor 1 (ROR1) is an attractive therapeutic target that is present on a range of haematological and solid malignancies, as well as cancer stem cells, but importantly with limited expression on normal adult tissues. Our aim, through iterative optimisation, was to generate novel humanised ROR1 single chain variable fragments (scFv) that enable efficient targeting of ROR1 on tumour cells without toxicity.Methods
13 novel anti-ROR1 antibodies were isolated after a rat immunisation programme, of which ten bound as scFvs. These fragments were engineered into a second generation CAR structure and using lentiviral vectors generated ROR1CAR T cells, imparting ROR1-specific but MHC-independent cytotoxicity. Concurrently, ROR1 scFvs were linked with a CD3 scFv to generate BiTEs—ie, small molecules able to facilitate formation of a cytotoxic synapse between T cells and ROR1+ tumour targets.Findings
Co-culture of our ten novel CAR T-cell constructs with ROR1+ target cells demonstrated scFv dependent cytotoxicity. Two lead candidates were selected for humanisation to minimise immunogenicity, and of 50 variants constructed one in particular was able to target haematological and solid tumour cell lines (p<0·0001 for ROR1+ Raji, PCL12, and Kasumi2 cell lines) with higher interleukin 2 secretion and superior specific cytotoxicity against primary chronic lymphocytic leukaemia cells compared with competitor constructs. In addition, our optimal humanised ROR1-BiTE mediated dose-dependent cytotoxicity against cell lines at low concentrations (1 ng/mL, p<0·0001 for SKW cells at 24 h). This BiTE decreased tumour burden and increased survival in an in-vivo model of aggressive lymphoma (median survival 50 days vs 18, p=0··0339).Interpretation
Extensive evaluation and optimisation has generated ROR1 CAR and BiTE constructs that can mediate potent effector function. Although both constructs harness the immune system, their unique characteristics provide a multifaceted platform to target a broad range of malignancies, many with considerable unmet therapeutic need such as pancreatic cancer. Ongoing work aims to determine which tumour types are best targeted by BiTEs or CAR T cells and to translate these agents to the clinic.Funding
Wellcome Trust, National Institute for Health Research, NHS Blood and Transplant. 相似文献12.
Ester Coutinho David Menassa Leslie Jacobson Steven West Joana Domingos Teresa Moloney Marianne G Pedersen Michael E Benros Bethan Lang David Bennett Paul J Harrison Preben B Mortensen Bent Nørgaard-Pedersen David Bannerman Angela Vincent 《Lancet》2017
Background
CNS disorders can be caused by IgG antibodies to neuronal surface proteins, and these antibodies have the potential to cross the placenta. Since some of them target proteins involved in neurodevelopment, such as contactin-associated protein-2 (CASPR2), we hypothesised that they could alter developing neuronal circuits in utero and lead to neurodevelopmental disorders in the children.Methods
A dual approach to the study was undertaken. First, we studied pregnancy serum samples from two population-based Danish cohorts: a cohort of women with postpartum psychosis and a cohort of mothers of children with mental retardation and other disorders of psychological development (MR–DPD), each with individually matched controls. We screened them for the presence of antibodies to CASPR2. Then, we assessed the effects of in-utero exposure to the antibodies in a mouse maternal-to-fetal model.Findings
The combined results from these two cohorts showed that maternal antibodies to CASPR2 were associated with an increased risk of MR–DPD in the children: eight (4·4%) of 182 mothers of MR–DPD children had CASPR2 antibodies compared with only three (0·9%) of 347 mothers of children without this diagnosis (p=0·01). This association was explored by injection of mouse dams with IgG purified from CASPR2-antibody-positive patients, or from healthy controls. The mouse offspring had long-term behavioural sequelae, manifested as deficits in social interaction and social activities, and increased repetitive, non-social behaviours. When they were culled at 12 months, their brains showed abnormal migration of cortical projection neurons, increased microglial activation, and reduction in the number of glutamatergic synapses, confirming that there had been long-term changes in neurodevelopment.Interpretation
CASPR2 was identified as a specific target for maternal antibodies that can alter brain development in utero, resulting in long-term behavioural deficits and permanent abnormalities at the cellular and synaptic level. These results should encourage further epidemiological and experimental studies to confirm and explore further how CASPR2 and other maternal antibodies can lead to neurodevelopmental disorders in children.Funding
EC was funded by the Programme for Advanced Medical Education at the Calouste Gulbenkian Foundation. This work was also supported by the Stanley Medical Research Institute. Resources were provided by the Nuffield Department of Clinical Neurosciences. 相似文献13.
Upkar S Gill Dimitra Peppa Lorenzo Micco Harsimran D Singh Nina Le Bert Laura Rivino Kamini Kunasegaran Damien Tan Antonio Bertoletti Mala K Maini Patrick T F Kennedy 《Lancet》2017
Background
There is a pressing need for new treatment strategies in chronic hepatitis B. Natural killer (NK) cells are important antiviral effectors, and are potently expanded with peginterferon alfa in chronic hepatitis B. Robust antiviral T-cell responses are crucial for resolution of this disease and can be expanded with nucleos(t)ide analogues (NAs). We assessed whether changes in the NK and T-cell pool would be altered when patients are primed with peginterferon alfa and whether these changes are modulated upon switching to sequential NAs.Methods
Peripheral blood mononuclear cells from 52 patients were analysed. 33 underwent a course of peginterferon alfa and were sampled longitudinally; 24 of them progressed to sequential NAs. 19 patients receiving de-novo NA therapy were analysed for comparison. NK cell subsets and global T cells were analysed by multicolour flow cytometry, and hepatitis B virus (HBV)-specific T cells were analysed by enzyme-linked immunospot assay and correlated with treatment outcomes.Findings
There was cumulative expansion of CD56bright NK cells driven by peginterferon alfa, which was maintained at higher than baseline concentrations throughout subsequent sequential NAs (p=0·0039). The expansion in proliferating, functional NK cells was more pronounced after sequential NAs compared with de-novo NAs. Patients treated with peginterferon alfa progressing to sequential NAs expressed higher levels of CD69, CD62L, and CXCR3 (implicated in antifibrogenesis) than did patients on de-novo therapy. Reduction in circulating HBsAg concentrations was only achieved in patients with enhancement of NK cell interferon γ and cytotoxicity. Partial recovery of HBV-specific T cells was seen during sequential NAs after peginterferon alfa cessation. Interestingly, no difference in the magnitude of HBV-specific T-cell responses was seen in patients on sequential NAs compared with de novo NAs.Interpretation
Peginterferon alfa priming expands a population of functional NK cells, with altered responsiveness to subsequent viral suppression by NAs. We have previously reported that NK cells can delete HBV-specific T cells, but our findings here suggest that the peginterferon alfa expanded NK cell pool does not exhibit this negative effect. We are investigating whether peginterferon alfa is able to protect T cells from NK cell attack, as demonstrated in a mouse model by other investigators.Funding
Wellcome Trust, Barts and The London Charity, National Medical Research Council Singapore. 相似文献14.
Nicholas J I Hamilton Dani Do Hyang Lee Kate H C Gowers Colin R Butler Robert E Hynds Martin A Birchall Sam M Janes 《Lancet》2017
Background
Tracheal reconstruction relies on the use of a split skin graft to re-epithelialise the mucosal layer. Since split skin grafts are made up of a keratinising stratified epithelial layer, sloughing occurs within the airway with mucus retention and subsequent airway obstruction. The delivery of a graft with the same mucociliary function as the native airway would overcome these limitations and greatly improve the safety and effectiveness of this type of surgery. We aimed to generate a transplantable tissue-engineered respiratory epithelial graft with mucociliary function.Methods
Cadaveric human skin was decellularised and the epidermal layer removed. Human bronchial epithelial cells were seeded with human respiratory fibroblasts onto the dermis at densities of 1?×?106 per cm2 and 1?×?104 per cm2, respectively, and cultured at air–liquid interface in a transwell system. At 3 weeks, the constructs were transplanted onto a decellularised trachea that had been prevascularised within a muscle wrap in an immunosuppressed New Zealand White rabbit.Findings
After 3 weeks of air–liquid interface culture, high-speed video microscopy showed beating cilia on the surface of the dermis, and the epithelial layer stained positively for the ciliated cell marker acetylated α-tubulin, the secretory cell marker MUC5AC, and the epithelial cell marker pan-cytokeratin on top-down whole-mount confocal microscopy. Staining with haematoxylin and eosin (H&E) demonstrated a pseudostratified mucociliary layer along the length of the dermis. 24 h after transplantation, a pseudostratified, ciliated layer could be observed on H&E staining of sections of trachea. At 5 days, the respiratory epithelial layer consisted of a single layer of cytokeratin 5-positive epithelial cells.Interpretation
This study is the first, to our knowledge, to report the delivery of a transplantable tissue-engineered respiratory epithelial graft with mucociliary function. 24 h after transplantation the mucociliary layer was preserved although only a basal layer was demonstrated by 5 days, possibly due to the loss of the air–liquid interface within the muscle wrap.Funding
Medical Research Council. 相似文献15.
Teresa Tsakok Tom Marrs Mahrose Mohsin Susannah Baron George du Toit Stephen Till Carsten Flohr 《Lancet》2017
Background
Atopic dermatitis is the commonest chronic inflammatory disorder of the skin, affecting more than 20% of children in industrialised countries and up to 5% of adults. This condition is often associated with other atopic diseases, such as IgE-mediated food allergy (FA). Food allergen recognition via antigen-presenting cells in eczematous skin has been suggested to act as an important mediator of food sensitisation and FA. This would have important implications for prevention and treatment. We aimed to review the association between atopic dermatitis and FA; the effect of FA on atopic dermatitis severity, chronicity, and age of onset; and whether there was a temporal association between atopic dermatitis and FA.Methods
A systematic search of Medline and Embase, with no language limits imposed, from inception until Nov 30, 2014, was supplemented by a hand search of the literature. Two authors independently screened abstracts for suitability, resulting in 164 articles that were read in full. Article selection for further analysis was based on specific inclusion and exclusion criteria. We extracted data from selected articles using a predefined proforma. Since we did not consider formal meta-analysis to be either feasible or appropriate, we assigned a quality score to each article.Findings
66 studies were identified. 18 were population based, eight used high-risk cohorts, and 40 comprised patients with either established atopic dermatitis or FA. In population-based studies, the likelihood of food sensitisation was up to six times higher in patients with atopic dermatitis than in healthy controls at 3 months of age (odds ratio 6·18, 95% CI 2·94–12·98; p<0·001). Studies that included only patients with established atopic dermatitis reported food sensitisation prevalences of up to 66%, with challenge-proven FA prevalences up to 81%. Results from 16 studies suggested that FA is associated with a more severe atopic dermatitis phenotype. Six studies indicated that atopic dermatitis of earlier onset or increased persistence is particularly associated with FA. Finally, results of one study indicated that atopic dermatitis preceded the development of FA.Interpretation
We confirm a strong and dose-dependent association between atopic dermatitis, food sensitisation, and FA. Atopic dermatitis of increased severity and chronicity is particularly associated with FA. Atopic dermatitis appeared to precede the development of FA, in keeping with a causal association. This evidence provides further support for skin barrier repair, early proactive treatment for atopic dermatitis, and reduction of environmental food allergen exposure in the prevention of food sensitisation and allergy.Funding
None. 相似文献16.
Background
The annual number of newly licensed doctors is an important indicator of medical workforce supply, which can accurately reflect an inflow into the health-care market during a time period. Since the implementation of the Law on Practicing Doctors in 1999, the Chinese Government has established its medical licensure system to both regulate medical professions and improve the quality of health-care services. We aimed to analyse the trend and structure of newly licensed doctors since the establishment of its medical licensure system.Methods
We analysed a unique census dataset that provides the headcount of newly licensed doctors in China between 2005 and 2015. We also review a short history of medical licensing system reform in China since the 1990s.Findings
The annual number of first-time licensed doctors in China increased from 159?489 in 2005 to 221?639 in 2015. Until 2015, more than 50% of newly licensed doctors had not received equivalent medical education of a bachelor degree or higher. In 2005, about 51% of China's newly licensed doctors were women, whereas in 2015, 56% newly licensed doctors were women.Interpretation
Our findings could inform policy making in human resources for health in at least two aspects. First, the heterogeneity of medical education of entering doctors needs to draw more attention of policy makers. The second policy implication is, however, that the feminisation of physician in China is becoming more apparent, and the consequences still require more rigorous examinations.Funding
None. 相似文献17.
Background
Long-acting injectable (LAI) antipsychotics have been shown to reduce risk of relapse in people with psychosis. Second generation LAI antipsychotics such as paliperidone palmitate can have fewer side-effects and be better tolerated than first generation LAI antipsychotics. However, paliperidone palmitate is more expensive and there are few data comparing its effectiveness and tolerability with that of other LAI antipsychotics. We sought to address this issue by analysing a large electronic mental health case register.Methods
The South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register was used to obtain data about people who had started treatment with an LAI antipsychotic between April 1, 2011, and Jan 31, 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were analysed using multivariable regression with age, sex, ethnicity, marital status, diagnosis, and London borough of residence as covariates.Findings
1281 people had started treatment with LAI antipsychotics. The most frequently prescribed LAI was paliperidone palmitate (n=430, 33·6%) followed by zuclopenthixol decanoate (226, 17·6%), flupentixol decanoate (203, 15·9%), risperidone (160, 12·5%), pipotiazine palmitate (114, 8·9%), haloperidol (71, 5·5%), fluphenazine decanoate (36, 2·8%), aripiprazole (27, 2·1%), and olanzapine embonate (14, 1·1%). There were no significant differences between paliperidone and other LAI antipsychotics in the number of days as an inpatient (β coefficient 5·4 days, 95% CI ?57·3 to 68·2) or number of hospital admissions after initiation of treatment (incidence rate ratio 1·07, 95% CI 0·62 to 1·83).Interpretation
The absence of differences in hospital admission after initiation of LAI antipsychotics indicates that the effectiveness of the second generation LAI paliperidone palmitate was similar to that of other LAI antipsychotics. However, the discontinuation rate in the first year of treatment is lower for paliperidone palmitate (35%) than for other LAI antipsychotics suggesting that it is better tolerated. These findings merit consideration in relation to the choice of LAI antipsychotic to prescribe in people with psychotic disorders.Funding
National Institute for Health Research, Medical Research Council. 相似文献18.
Background
There is no standardised instrument for assessing social functioning in dementia, even though decline in social functioning is one of the diagnostic criteria for dementia and important to patients and their families. We aimed to develop a valid, reliable, acceptable instrument for assessing social function in people with dementia.Methods
We conducted qualitative interviews with 18 dyads of people with dementia and their family carers, a literature review, and focus groups with expert health-care professionals to develop the Social Functioning in Dementia (SF-DEM) instrument. SF-DEM measures the social functioning of a person with dementia using their own rating or a family carer's rating. We tested acceptability and psychometric properties of these measures in structured interviews at baseline and at 4 weeks' and 6–8 months' follow-up in a cohort of 30 dyads of people with mild dementia and their carers.Findings
SF-DEM had content validity. The instrument was acceptable to both patients and carers, who all rated it as acceptable or very acceptable. Inter-rater agreement was good or very good for all questions. Test–retest reliability was very strong for the carer-rated SF-DEM (intraclass correlation coefficient 0·89, 95% CI 0·73 to 0·96) and patient-rated version (0·80, 0·54 to 0·92), and both versions had internal consistency (Cronbach's α=0·71 for carer-rated SF-DEM and 0·64 for patient-rated). SF-DEM had concurrent validity, since it was moderately correlated with a question about overall social functioning (r=0·60, 95% CI 0·29 to 0·78 for carer-rated; 0·44, 0·07 to 0·68 for patient-rated). SF-DEM also had convergent validity, as evidenced by a moderate correlation between patient and carer ratings (r=0·59, 95% CI 0·07 to 0·81). At follow-up (mean duration 7·2 months, SD 0·5), patient-rated SF-DEM score increased by 1·3 points (95% CI ?0·3 to 2·9, p=0·10) and caregiver-rated SF-DEM score increased by 1·4 points (?0·1 to 2·9, p=0·06) for each point on a five point ordinal scale of social change.Interpretation
Patient-rated and carer-rated versions of the SF-DEM are reliable, valid, and acceptable measures of social function in people with mild dementia. Further research is required to test the generalisability to other populations.Funding
None. 相似文献19.
Background
Over 8·75 million people in the UK live with osteoarthritis, which has major social and economic costs. Although the current approach to managing this condition in primary care is suboptimal, any quality improvement must deliver value for money. Social return on investment (SROI) is a cost-benefit analysis that captures wider social benefits. Here, we describe a SROI analysis of a physiotherapy-led service (rather than the usual general practitioner [GP]-led model) delivering National Institute for Health and Care Excellence (NICE) guidance for managing osteoarthritis in six GP practices.Methods
SROI analysis was undertaken to determine the inputs, outputs, and outcomes associated with the intervention. These data were used to calculate a SROI ratio, which determined the level of social value created for every £1 of investment. To mitigate the risk of overclaiming any benefits created by the service, the calculation used conservative values and accounted for deadweight, displacement, drop-off, and attribution. A sensitivity analysis was performed and the SROI was externally validated.Findings
The SROI analysis showed that a physiotherapy-led service that delivers advice in line with NICE guidance created levels of social value that were greater than the cost of investment. Every £1 invested into the service resulted in a return of £2·43 to £4·03 in social value. The benefits (or outcomes) that patients gained from using the service were increased levels of physical activity, improved physical and mental health, reduced pain, and the saving in money and time spent travelling by accessing a local (GP-based) service. Outcomes for the National Health Service (NHS) were a reduction in health utilisation (eg, fewer GP consultations and secondary referrals) and the saving gained from the levels of weight loss seen in patients (ie, savings dispersed within the wider health system).Interpretation
SROI analysis shows that a physiotherapy-led service in primary care that delivers NICE guidance for managing osteoarthritis created an SROI for patients and the NHS. The service delivered benefits to patients, reduced health utilisation elsewhere in the system (eg, GP workload), and delivered value for money. SROI can provide a useful approach to support funding bodies to determine cost-effectiveness for commissioning services in health care.Funding
Health Innovation Network. 相似文献20.
Sean Sylvia Hao Xue Chengchao Zhou Yaojiang Shi Hongmei Yi Huan Zhou Scott Rozelle Madhukar Pai Jishnu Das 《Lancet》2017