Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.Peer reviewedFinal Accepted Versio

Up-regulation of 14-3-3sigma (Stratifin) is associated with high-grade CIN and high-risk human papillomavirus (HPV) at baseline but does not predict outcomes of HR-HPV infections or incident CIN in the LAMS study

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV.LAMS, Latin American Screening Study, funded by European Commission, INCO-DEV contract ICA4-CT-2001-10013

Up-Regulation of Plasminogen Activator Inhibitor-2 Is Associated With High-Risk HPV and Grade of Cervical Lesion at Baseline but Does Not Predict Outcomes of High-Risk HPV Infections or Incident CIN

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The Hep-CORE policy score: A European hepatitis C national policy implementation ranking based on patient organization data.

BACKGROUND content: New hepatitis C virus (HCV) treatments spurred the World Health Organization (WHO) in 2016 to adopt a strategy to eliminate HCV as a public health threat by 2030. To achieve this, key policies must be implemented. In the absence of monitoring mechanisms, this study aims to assess the extent of policy implementation from the perspective of liver patient groups. - Label: METHODS content: "Thirty liver patient organisations, each representing a country, were surveyed in October 2018 to assess implementation of HCV policies in practice. Respondents received two sets of questions based on: 1) WHO recommendations; and 2) validated data sources verifying an existing policy in their country. Academic experts selected key variables from each set for inclusion into policy scores. The similarity scores were calculated for each set with a multiple joint correspondence analysis. Proxy reference countries were included as the baseline to contextualize results. We extracted scores for each country and standardized them from 0 to 10 (best)." - Label: RESULTS content: Twenty-five countries responded. For the score based on WHO recommendations, Bulgaria had the lowest score whereas five countries (Cyprus, Netherlands, Portugal, Slovenia, and Sweden) had the highest scores. For the verified policy score, a two-dimensional solution was identified; first dimension scores pertained to whether verified policies were in place and second dimension scores pertained to the proportion of verified policies in-place that were implemented. Spain, UK, and Sweden had high scores for both dimensions. - Label: CONCLUSIONS content: Patient groups reported that the European region is not on track to meet WHO 2030 HCV goals. More action should be taken to implement and monitor HCV policies

Determinants of the accuracy of rapid diagnostic tests in malaria case management: evidence from low and moderate transmission settings in the East African highlands

BACKGROUND: The accuracy of malaria diagnosis has received renewed interest in recent years due to changes in treatment policies in favour of relatively high-cost artemisinin-based combination therapies. The use of rapid diagnostic tests (RDTs) based on histidine-rich protein 2 (HRP2) synthesized by Plasmodium falciparum has been widely advocated to save costs and to minimize inappropriate treatment of non-malarial febrile illnesses. HRP2-based RDTs are highly sensitive and stable; however, their specificity is a cause for concern, particularly in areas of intense malaria transmission due to persistence of HRP2 antigens from previous infections. METHODS: In this study, 78,454 clinically diagnosed malaria patients were tested using HRP2-based RDTs over a period of approximately four years in four highland sites in Kenya and Uganda representing hypoendemic to mesoendemic settings. In addition, the utility of the tests was evaluated in comparison with expert microscopy for disease management in 2,241 subjects in two sites with different endemicity levels over four months. RESULTS: RDT positivity rates varied by season and year, indicating temporal changes in accuracy of clinical diagnosis. Compared to expert microscopy, the sensitivity, specificity, positive predictive value and negative predictive value of the RDTs in a hypoendemic site were 90.0%, 99.9%, 90.0% and 99.9%, respectively. Corresponding measures at a mesoendemic site were 91.0%, 65.0%, 71.6% and 88.1%. Although sensitivities at the two sites were broadly comparable, levels of specificity varied considerably between the sites as well as according to month of test, age of patient, and presence or absence of fever during consultation. Specificity was relatively high in older age groups and increased towards the end of the transmission season, indicating the role played by anti-HRP2 antibodies. Patients with high parasite densities were more likely to test positive with RDTs than those with low density infections. CONCLUSION: RDTs may be effective when used in low endemicity situations, but high false positive error rates may occur in areas with moderately high transmission. Reports on specificity of RDTs and cost-effectiveness analyses on their use should be interpreted with caution as there may be wide variations in these measurements depending upon endemicity, season and the age group of patients studied

Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity

Does the spillage of petroleum products in Anopheles breeding sites have an impact on the pyrethroid resistance?

<p>Abstract</p> <p>Background</p> <p>The emergence of <it>Anopheles </it>populations capable of withstanding lethal doses of insecticides has weakened the efficacy of most insecticide based strategies of vector control and, has highlighted the need for further studies on the mechanisms of insecticide resistance and the various factors selecting resistant populations of mosquitoes. This research targeted the analysis of breeding sites and the oviposition behaviour of susceptible and resistant populations of <it>Anopheles </it>in localities of spilled petroleum products. The aim was to establish the possible contribution of oil spillage in the selection of pyrethroid resistance in malaria vectors.</p> <p>Methods</p> <p><it>Anopheles </it>breeding sites were identified and the insecticide susceptibility of the <it>Anopheles gambiae </it>populations mapped in 15 localities of South Western Nigeria. The presence of oil particles as well as the turbidity, the dissolved oxygen and the pH of each identified breeding site was recorded. Data were cross-analysed to correlate the habitat types and the insecticide susceptibility status of emerging mosquitoes. The second phase of this study was basically a laboratory model to provide more information on the implication of the spillage of petroleum on the selection of pyrethroid resistance in <it>An. gambiae</it>.</p> <p>Results</p> <p>Moderate levels of resistance following exposure to permethrin-impregnated papers were recorded with the majority of <it>An. gambiae </it>samples collected in the South Western Nigeria. Data from this study established a link between the constituency of the breeding sites and the resistance status of the emerging <it>Anopheles</it>.</p> <p>Conclusion</p> <p>This study has revealed the segregational occupation of breeding habitats by pyrethroid resistant and susceptible strains of <it>An. gambiae </it>in south-western Nigeria. Compiled results from field and laboratory research point out clear relationships between oil spillage and pyrethroid resistance in malaria vectors. The identification of this factor of resistance could serve as strong information in the management of insecticide resistance in some West African settings.</p

Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe

Background Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. Methods Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final “bacterial” or “viral” phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. Results Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the “Watch” category. Conclusions Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship