Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease.

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Increased Risk of High-grade Cervical Neoplasia in Women with Inflammatory Bowel Disease: A Case-controlled Cohort Study.

BACKGROUND AND AIMS: Women with inflammatory bowel disease [IBD] may be at higher risk for cervical intraepithelial neoplasia [CIN]. However, data are conflicting. The aim of this study was to assess the risk of high-grade dysplasia and cancer [CIN2+] in IBD women and identify risk factors. METHODS: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort [PSI] from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database [PALGA], from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates [SDR] were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios [IRR] and risk factors were identified in multivariable analysis. RESULTS: Cervical records were available from 2098 IBD women [77%] and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval [CI] 1.05-1.52). Women with IBD had an increased risk of CIN2+ [IRR 1.66, 95% CI 1.21-2.25] and persistent or recurrent CIN during follow-up (odds ratio [OR] 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic [L3] or upper gastrointestinal [GI] [L4]). CIN2+ risk was not associated with exposure to immunosuppressants. CONCLUSIONS: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus [HPV] vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.

Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes. METHODS: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B. RESULTS: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04]. CONCLUSIONS: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.

Functional or not functional; that's the question: Can we predict the diagnosis functional movement disorder based on associated features?

BACKGROUND AND PURPOSE: Functional movement disorders (FMDs) pose a diagnostic challenge for clinicians. Over the years several associated features have been shown to be suggestive for FMDs. Which features mentioned in the literature are discriminative between FMDs and non-FMDs were examined in a large cohort. In addition, a preliminary prediction model distinguishing these disorders was developed based on differentiating features. METHOD: Medical records of all consecutive patients who visited our hyperkinetic outpatient clinic from 2012 to 2019 were retrospectively reviewed and 12 associated features in FMDs versus non-FMDs were compared. An independent t test for age of onset and Pearson chi-squared analyses for all categorical variables were performed. Multivariate logistic regression analysis was performed to develop a preliminary predictive model for FMDs. RESULTS: A total of 874 patients were eligible for inclusion, of whom 320 had an FMD and 554 a non-FMD. Differentiating features between these groups were age of onset, sex, psychiatric history, family history, more than one motor phenotype, pain, fatigue, abrupt onset, waxing and waning over long term, and fluctuations during the day. Based on these a preliminary predictive model was computed with a discriminative value of 91%. DISCUSSION: Ten associated features are shown to be not only suggestive but also discriminative between hyperkinetic FMDs and non-FMDs. Clinicians can use these features to identify patients suspected for FMDs and can subsequently alert them to test for positive symptoms at examination. Although a first preliminary model has good predictive accuracy, further validation should be performed prospectively in a multi-center study.

Safety of Anti-TNF Treatment in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Little is known about the risk of serious infection when combining anti-tumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. METHODS: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. RESULTS: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti-TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. CONCLUSIONS: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy.

The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour.

AIMS: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved in the migration of immune cells in the injured brain, they may also be involved in chemoattraction of NSCs towards a brain tumour. METHODS: The expression profile of various chemokine receptors in NSCs, harvested from the subventricular zone of adult mice, was investigated by reverse transcriptase- polymerase chain reaction analysis. Furthermore, the functionality of the chemokine receptors was assessed in in vitro chemotaxis assays and calcium signalling experiments. To test the in vivo migration of NSCs, a syngeneic mouse model was developed, whereby a B16F10 melanoma cell line was grafted into one hemisphere and later NSCs were grafted in the contralateral hemisphere. Furthermore, the expression of chemokines in this melanoma cell line was investigated. RESULTS AND CONCLUSIONS: Adult mouse NSCs functionally express various chemokine receptors of which CXC chemokine receptor (CXCR)4 shows the highest mRNA levels and most pronounced functional responses in vitro. CXC chemokine ligand (CXCL)12, the ligand for CXCR4, is expressed by the melanoma cell line. In this mouse model for metastatic brain tumours, it is shown that NSCs express CXCR4 at their cell membranes while they migrate towards the tumour, which produces CXCL12. It is therefore suggested that the CXCR4/CXCL12 pathway plays a role in the mechanism underlying tumour-mediated attraction of NSCs.

The Greater Involvement of People Living with AIDS principle: theory versus practice in Ontario's HIV/AIDS community-based research sector.

Drawing on the Greater Involvement of People with HIV/AIDS (GIPA) principle, the HIV/AIDS movement began to "democratize" research in Canada in the mid-1990s. To date, there is little evidence about the success of the community-based research (CBR) movement in relation to the implementation of GIPA. We draw on findings from a larger study examining barriers and facilitating factors in relation to HIV-related CBR in Ontario, Canada. An online survey was completed by 39 senior managers in Ontario AIDS service organizations (ASOs). Twenty-five in-depth, semi-structured interviews were then conducted to further explore the survey findings. Survey respondents reported that, compared to researchers and frontline service providers, people living with HIV/AIDS (PLWHA) tended to be the least involved in all stages (input, process and outcome) of CBR projects. AIDS service organizations with a mandate that included serving rural and urban communities reported even lower levels of PLWHA involvement in CBR. Qualitative data reveal complex barriers that make meaningful PLWHA engagement in CBR difficult, including: HIV-related stigma; health-related challenges; "credentialism"; lack of capacity to engage in research; other issues taking priority; and mistrust of researchers. Facilitating factors included valuing lived experience; training and mentoring opportunities; financial compensation; trust building; and accommodating PLWHA's needs. While there is strong support for the GIPA principles in theory, practice lags far behind.

Evaluation of three enzyme-linked immunosorbent assays for detection of antibodies to Neospora caninum in bulk milk.

Three ELISAs for the detection of antibodies against Neospora caninum in bulk milk were evaluated in 162 Dutch dairy herds. The first ELISA was the Dutch Animal Health Service (AHS) in-house ELISA, developed from the routine in-house serum ELISA. The other two ELISAs were commercial milk ELISAs from IDEXX and LSI. Blood samples of all lactating cows in 162 dairy herds were tested using the AHS in-house serum ELISA. Based on previous studies in the Netherlands a within-herd N. caninum seroprevalence of 15% was associated with increased risk for reproductive losses. This percentage was therefore used as positive seroprevalence cut-off value. Repeatability of the ELISAs was evaluated by testing on three different days. The AHS in-house ELISA lacked specificity, probably due to use of a different batch of antigen on the second and third test-day. Cut-off values were determined using misclassification costs term calculations. At cut-off values 0.6 for the IDEXX and 0.2 for the LSI, a herd sensitivity of 61% (95% CI: 49--73%) and 47% (95% CI: 35--60%) was estimated. Herd specificity at these cut-off values was 92% (95% CI: 87--98%) for the IDEXX and 94% (95% CI: 90--99%) for the LSI ELISA. The positive and negative predictive values were 84% (95% CI: 68--100%) and 86% (95% CI: 79--94%) for the IDEXX ELISA, and 85% (95% CI: 67--100%) and 82% (95% CI: 74--90%) for the LSI ELISA. The agreement between all possible combinations of test-days was expressed by kappa values. These were found to be slightly higher for the IDEXX than for the LSI ELISA. It is concluded that both commercial ELISAs performed satisfactorily to detect a within-herd seroprevalence of N. caninum in lactating cows of at least 15%.

Reduction of donor-specific cytotoxic T lymphocyte precursors in peripheral blood of allografted heart recipients.

Tolerance to allografted hearts in human recipients has been observed both in clinical situations and in in vitro experiments. To elucidate whether a quantitative change of alloreactive CTL is one of the mechanisms accounting for this graft tolerance, CTL precursor (CTLp) frequencies in the peripheral blood of 10 heart recipients were measured against spleen cells from donors and HLA nonidentical third-party persons. In this longitudinal follow-up study, we showed that the rejection reaction(s) in the grafted heart correlated with CTLp frequencies in samples taken before transplantation against the donor spleen cells, but not with the CTLp frequencies against the spleen cells from the third-party persons. The CTLp frequencies against the spleen cells from donors decreased 4-6 months after transplantation, and remained at a low level afterward. However, the CTLp frequencies against spleen cells from third-party persons in blood samples obtained 1 year after transplantation were not significantly different from those before transplantation. Therefore, we conclude that donor-reactive CTLs are important in rejecting allografted heart. The decrease in donor-specific CTLp after transplantation could explain the donor-specific tolerance. The decrease may be due to homing of the specific CTLp to the graft, or by clonal deletion of the donor-reactive CTL caused by chronic alloantigen stimulation in the presence of immunosuppressive therapies.

Soluble CD8 and CD25 in serum of patients after heart transplantation.

To evaluate the diagnostic value of serum cytokine levels and cytokine receptor levels in the diagnosis of acute rejection after heart transplantation, we measured soluble CD8 and soluble CD25 in the serum of heart transplant recipients. The results were compared with endomyocardial biopsy (EMB) histopathology, lymphocyte activation by morphologic inspection of peripheral blood cells (cytoimmunologic monitoring), clinically manifested infections, and the maintenance immunosuppressive therapy. Significantly increased levels were observed in cases of lymphocyte activation in cytoimmunologic monitoring indicative of either rejection or infection. In clinically documented cytomegalovirus (CMV), bacterial, and Pneumocystis carinii infections, increased levels of soluble CD25 were observed. Soluble CD8 was only increased in a single case of P. carinii infection. A statistically significant correlation was calculated between the levels of soluble CD8 and whole blood cyclosporin A level. Considering chemotherapy, the levels of soluble CD8 showed an inverse correlation with the daily dosage of azathioprine. In conclusion, the levels of soluble CD8 and CD25 are associated with lymphocyte activation in peripheral blood, but do not differentiate between lymphocyte activation indicative of rejection or infection. No relationship was observed between levels of soluble CD8 and CD25, and EMB histopathology. Therefore, the assessment of these two cell products has no diagnostic potential for monitoring acute rejection after heart transplantation.

Cytoimmunologic monitoring as an adjunct in monitoring rejection after heart transplantation: results of a 6-year follow-up in heart transplant recipients.

The cytoimmunologic monitoring assay has been proposed as a useful noninvasive technique in the diagnosis of rejection and infection after heart transplantation. In this study, we have analyzed the diagnostic usefulness of cytoimmunologic monitoring in 73 patients after heart transplantation. For individual patients, the follow-up varied between 2 and 78 months. Data were related to histopathologic characteristics of the endomyocardial biopsy. Significantly different cytoimmunologic monitoring results were not observed between groups according to endomyocardial biopsy histopathologic evaluation. The diagnostic usefulness of cytoimmunologic monitoring depended on the cutoff value applied. With higher cutoff values, the sensitivity decreased and the specificity and predictive value increased. For the previously reported cutoff value of 5%, the sensitivity was 0.29, the specificity was 0.73, and the predictive value was 0.66. Values of sensitivity, specificity, and predictive value were similar when only the first acute rejection was taken into account, or when only data on the first 4 weeks and the first 6 months after transplantation were considered. In calculating the diagnostic usefulness of the sensitivity, specificity, and predictive values were observed. We concluded that cytoimmunologic monitoring has a limited value for diagnosing acute rejection after heart transplantation.

Endomyocardial biopsies after heart transplantation. The presence of markers indicative of activation.

A series of 104 endomyocardial biopsies (EMB) from patients after heart transplantation was evaluated for the presence of immunological markers on graft component and infiltrating cells. This included markers for cells expressing alpha beta-T-cell receptors and gamma delta-T-cell receptors, and cytotoxic T cells with granules bearing the serine esterase Granzyme B; the presence of activation markers identified by CD25 (interleukin 2 receptor), CD30, CD69 (activation inducer molecule), CDw70; macrophages using antibody CD14 (WT14), and cells with Fc gamma-receptors type III (CD16). Almost all cells in T-cell infiltrates expressed the alpha beta-T cell receptor. Cells bearing the gamma delta-T cell receptor were scarcely found. The analysis with respect to the histopathologic diagnosis for rejection showed an absence of significance for T cell subsets, Granzyme B-positive cells, and activation markers except CD25. The numbers of macrophages labeled by CD14 and cells expressing Fc gamma RIII showed a significant relation to histopathology of rejection. Apart from leukocytes, also endothelium in EMB with rejection was labeled by the two anti-Fc gamma RIII antibodies used. In addition, in a small series of biopsies investigated, Fc gamma RI- and Fc gamma RII-positive cells were increased in EMB with rejection, and endothelium was labeled by Fc gamma RII antibodies. A cluster analysis on the basis of scores for CD25, CD14, and anti-Fc gamma RIII revealed three main clusters, one cluster comprising biopsies without abnormalities, one cluster containing EMB with the histopathology of rejection and high scores in immunophenotyping for lymphocytes and macrophages, and one cluster in between. The present data emphasize the importance of macrophage assessment in evaluating pathologic processes during rejection of heart allografts and diagnosing rejection.

Low birth weight assessment in Chatinkha maternity wing

The aims of this study were to assess the incidence of LBW in the Gogo Chatinkha Banda Maternity wing of Queen Elizabeth Central Hospital(Chatinkha Martenity Wing) in Blantyre; to subdivide the LBW infants into preterm and TSGA groups; and to use the results to make suggestions for optimal management of LBW at Chatinkha Maternity Wing

A field intercomparison and fundamental characterization of various dust samplers with a reference sampler.

The European Economic Community Council Directive 80/779/EEC describes air quality limit values and guide values for sulfur dioxide and suspended particulates. However, article 10, paragraph 1 does not define well enough the reference method required, amongst others, for the gravimetric measurement of suspended particulates. It is explicity stated in article 10, paragraph 5 of the directive, that "the commission shall, in selected locations in the member states and in cooperation with the latter, carry out studies on the sampling...of suspended particulates. These studies shall be designed in particular to promote the harmonization of methods of sampling and analysis of these pollutants." Therefore, in a joint research program the Umweltbundesamt (grant #104 02263), the commission of European Communities (grant #84-B-6642-11-017-11-N) and the U.S. EPA (grant #2-432U-3580) funded the development of a reference dust sampler by the Fraunhofer-Institute of Toxicology and Aerosol Research (FhlTA, in Hannover, Federal Republic of Germany) in order: to study the particle size distribution of ambient air aerosol at a number of selected sites; to compare the results obtained with the reference dust sampler with those of particle samplers operated in Europe and the United States; to verify the applicability of wind tunnel results to sampling behaviour in the free atmosphere.

Monitoring rejection after heart transplantation: cytoimmunological monitoring on blood cells and quantitative birefringence measurements on endomyocardial biopsy specimens.

Cytoimmunological monitoring and quantitative birefringence measurements were used as potential aids in diagnosing acute rejection after heart transplantation instead of histopathological assessment of the endomyocardial biopsy specimen alone. Cytoimmunological monitoring was based on morphological inspection and quantitation of mononuclear cells, particularly activated lymphoid cells. Quantitative birefringence measurements comprise a variable for myocyte contractile function. Its read out is the ratio of the degree of birefringence before contraction to that after. Cytoimmunological monitoring indicated significantly higher concentrations of activated lymphocytes in moderate or severe acute rejection, and quantitative birefringence measurements indicated decreased myocyte function during severe and resolved or resolving rejection. Cytoimmunological monitoring and quantitative birefringence measurements were diagnostically most useful in terms of sensitivity, specificity, and predictive value, when only data gathered before the first episode of acute rejection were considered. For cytoimmunological monitoring, diagnostic relevance was optimal when the data were expressed as relative proportions of activated lymphocytes. The quantitative birefringence measurements correlated best with analysis of the endomyocardial biopsy specimen when a cut off value of 1.25 was used. When both methods for diagnosing acute rejection were analysed together, no improvement in sensitivity (value 0.44) was found, but the specificity increased to 0.98 and the predictive value to about 0.80. It is concluded that cytoimmunological monitoring is a useful, non-invasive additional method for diagnosing the first period of acute rejection after heart transplantation and that quantitative birefringence measurements give valuable information on the extent of myocyte damage.

Lymphocyte status in endomyocardial biopsies and blood after heart transplantation.

We performed immunological phenotyping of mononuclear cells in tissue sections of 84 endomyocardial biopsies (EMB) showing infiltrates, which were taken from 21 patients after heart transplantation. Data were correlated with histology (grading following Billingham) and cyto-immunologic monitoring (CIM) on blood samples (grading into negative, rejection, or infection, based on leukocyte morphology and T-cell phenotype). Few T lymphocytes were observed in 35 biopsies, and many in 49 biopsies. The semi-quantitative estimate of T cells and CD4/CD8 ratio did not correlate with EMB histology but was related to CIM data. For example, 31 out of 42 cases with a CIM indicative of infection (14 of which showing no rejection on histology) manifested large numbers of T cells. In most cases, the CD4/CD8 ratio was less than 1. The presence of activated cells (bearing interleukin-2 receptors or the CD30 antigen) was not related to EMB histology or to CIM data. The number of T cells (subsets) in EMB was not related to relative or absolute numbers in the blood.

Endomyocardial biopsies after heart transplantation. The presence of immunoglobulin/immune complex deposits.

A series of 221 endomyocardial biopsies (EMB), taken from 21 patients after heart transplantation, was analyzed for the presence of immunoglobulin/immune complex deposits. Data were correlated with histology (grading following Billingham) and cytoimmunologic monitoring (CIM) on blood samples (grading into negative, rejection, or infection, based on leukocyte morphology and T cell phenotype). IgM deposits and IgG/IgM complexes in blood capillaries around myocyte fibrils were found in 78 and 40 EMB, respectively. This feature was more prevalent in EMB with a histology of rejection (39 out of 52 biopsies).