Central Corneal Thickness: A Retrospective Comparison of Handheld Ultrasound Pachymetry and Optical Biometric Analysis Measurements

Purpose To determine if the measure of central cornea thickness among suspected and confirmed glaucomatous patients is significantly influenced by instrument device. Methods We retrospectively examined the charts of all patients having a central corneal thickness (CCT) measured with both ultrasound pachymetry and IOL Master 700 at the Kresge Eye Institute within the past year. Intraocular pressure and demographic data including age and race, were also collected. Significant corneal disease such as Fuchs corneal dystrophy, other corneal dystrophies, corneal transplant, and corneal edema were excluded. Statistical analysis of the paired CCT measurements were performed with a paired t-test and regression analysis. Results The total number of patients having a CCT measured with both ultrasound pachymetry and IOLMaster700 was 59. Mean CCT measured with ultrasound pachymetry was 539.38 ± 49.56 µm (n=118). Mean CCT measured with IOLMaster700 was 536.83 ± 42.52 µm (n=112). The intraparticipant mean of differences between the ultrasound pachymetry and the IOLMaster700 was 3.16 ± 25 µm. Analysis with a paired t-test did not find a significant difference between the two groups (p=0.19). A regression analysis of the paired CCTs yielded an R2 value of 0.74. Conclusion There is no significant difference between CCT measurements taken with handheld ultrasound pachymetry compared to the IOL Master 700. More data is warranted to confirm, but the IOL Master 700 may yield lower variability and a lower mean CCT, possibly due to greater instrument precision and increased likelihood of a central measurement. In practice, the IOL Master 700 may provide a more reliable measure of central cornea thickness when compared with ultrasound pachymetry

The impact of culture and sociological and psychological issues on Muslim patients with breast cancer in Pakistan

This is a non-final version of an article published in final form in Cancer Nursing, 32(4), 2009. The final published article is available from the link below.Breast cancer is the most common form of cancer in Muslim women in Pakistan. The impact of the initial diagnosis, culture, religion, and psychosocial and psychological aspects of the disease is not well established. This qualitative study examined the experience and coping strategies used by patients with breast cancer in relation to its impact on their physical, mental health, religious, and family issues. Thirty patients with breast cancer were interviewed. Data were analyzed using thematic analysis. The patient's experience of breast cancer focused on the range of emotions felt throughout the illness trajectory, the importance of religion and family support on coping strategies used to manage the adverse effects of chemotherapy, and also the financial concerns. This is the first study to examine Pakistani Muslim women's views on the lived experience of breast cancer. This article provides clarification of the voiced experiences of women with breast cancer. The data not only highlight the role of religion and family support as essential coping strategies but also emphasize the issues of isolation, aggression, and anger as common responses to chemotherapy. Unique features of this study are women's need to seek spiritual support for their illness and the overriding innate characteristic of maternal responsibility. These cultural features require further analysis and research

Protection conferred by typhoid fever against recurrent typhoid fever in urban Kolkata.

We evaluated the protection conferred by a first documented visit for clinical care of typhoid fever against recurrent typhoid fever prompting a visit. This study takes advantage of multi-year follow-up of a population with endemic typhoid participating in a cluster-randomized control trial of Vi capsular polysaccharide typhoid vaccine in Kolkata, India. A population of 70,566 individuals, of whom 37,673 were vaccinated with one dose of either Vi vaccine or a control (Hepatitis A) vaccine, were observed for four years. Surveillance detected 315 first typhoid visits, among whom 4 developed subsequent typhoid, 3 due to reinfection, defined using genomic criteria and corresponding to -124% (95% CI: -599, 28) protection by the initial illness. Point estimates of protection conferred by an initial illness were negative or negligible in both vaccinated and non-vaccinated subjects, though confidence intervals around the point estimates were wide. These data provide little support for a protective immunizing effect of clinically treated typhoid illness, though modest levels of protection cannot be excluded

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850

High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Unmasking herd protection by an oral cholera vaccine in a cluster-randomized trial.

BACKGROUND: Several studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection on vaccinees and herd protection on populations. Because our earlier cluster-randomized effectiveness trial (CRT) in urban Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis. METHODS: A total of 267 270 persons were randomized to 90 approximately equal-sized clusters. In 60 clusters persons aged 1 year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesized that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households. RESULTS: During 2 years of follow-up of all residents of the clusters, total protection (protection of OCV recipients relative to control residents) was 58% [95% confidence interval (CI): 43%, 70%; P<0.0001], indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: -20%, 41%; P=0.35) and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI: 30%, 59%; P<0.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI: 50%, 87%, P<0.0001), indirect protection 52% (95% CI: -9%, 79%; P=0.08) and overall protection 72% (95% CI: 49%, 84%; P<0.0001) for the innermost 25% households. CONCLUSION: Consistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines

Use of oral cholera vaccine as a vaccine probe to determine the burden of culture-negative cholera.

Analyses of stool from patients with acute watery diarrhea (AWD) using sensitive molecular diagnostics have challenged whether fecal microbiological cultures have acceptably high sensitivity for cholera diagnosis. If true, these findings imply that current estimates of the global burden of cholera, which rely largely on culture-confirmation, may be underestimates. We conducted a vaccine probe study to evaluate this possibility, assessing whether an effective killed oral cholera vaccine (OCV) tested in a field trial in a cholera-endemic population conferred protection against cholera culture-negative AWD, with the assumption that if cultures are indeed insensitive, OCV protection in such cases should be detectable. We re-analysed the data of a Phase III individually-randomized placebo-controlled efficacy trial of killed OCVs conducted in Matlab, Bangladesh in 1985. We calculated the protective efficacy (PE) of a killed whole cell-only (WC-only) OCV against first-episodes of cholera culture-negative AWD during two years of post-dosing follow-up. In secondary analyses, we evaluated PE against cholera culture-negative AWD by age at vaccination, season of onset, and disease severity. In this trial 50,770 people received at least 2 complete doses of either WC-only OCV or placebo, and 791 first episodes of AWD were reported during the follow-up period, of which 365 were culture-positive for Vibrio cholerae O1. Of the 426 culture-negative AWD episodes, 215 occurred in the WC group and 211 occurred in the placebo group (adjusted PE = -1.7%; 95%CI -23.0 to 13.9%, p = 0.859). No measurable PE of OCV was observed against all or severe cholera culture-negative AWD when measured overall or by age and season subgroups. In this OCV probe study we detected no vaccine protection against AWD episodes for which fecal cultures were negative for Vibrio cholera O1. Results from this setting suggest that fecal cultures from patients with AWD were highly sensitive for cholera episodes that were etiologically attributable to this pathogen. Similar analyses of other OCV randomized controlled trials are recommended to corroborate these findings

Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft mode

Re-evaluating herd protection by Vi typhoid vaccine in a cluster randomized trial.

BACKGROUND: In a cluster randomized trial (CRT) of a Vi polysaccharide vaccine against typhoid in the slums of Kolkata we found evidence of vaccine herd protection. However, transmission of typhoid into clusters from the outside likely occurred in this densely populated setting, which could have diminished our estimates of vaccine herd protection. METHODS: Eighty clusters (40 in each arm) were randomised to receive a single dose of either Vi or inactivated hepatitis A vaccine. We analysed protection for the entire cluster and for subclusters consisting of residents of the innermost households. RESULTS: During 2 y of follow-up, total protection was 61% (95% CI 41 to 75), overall protection was 57% (95% CI 37 to 71) and indirect protection was 44% (95% CI 2 to 69). Analyses of the innermost 75% and 50% of households of the clusters showed similar findings. However, in the innermost 25% of households of the clusters, total protection was 82% (95% CI 48 to 94) and overall protection was 66% (95% CI 27 to 84). There was not a sufficient sample size to demonstrate such a trend for indirect protection in these innermost households. CONCLUSIONS: The findings suggest that analyses of the entire cluster may have led to underestimation of herd protection against typhoid by Vi vaccine and that restriction of the analyses to the inner subclusters may have led to a more accurate estimation of vaccine herd effects