Antipyretic, parasitologic, and immunologic effects of combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating uncomplicated Plasmodium falciparum malaria

Sulfadoxine/pyrimethamine (SP) is increasingly used against malaria in sub-Saharan Africa because of chloroquine resistance. However, chloroquine may have a beneficial antipyretic effect. We therefore compared the combination of SP plus chloroquine, chloroquine alone, SP alone, and SP plus paracetamol in the treatment of uncomplicated Plasmodium falciparum malaria in 175 Tanzanian children (1-4 years old) in a randomized trial. Outcome variables were axillary temperatures every six hours, daily parasitemias, and serum levels of IgG antibodies to P. falciparum. Lower mean temperatures (6-48 hours) were achieved with SP plus chloroquine or paracetamol than with SP alone (P \u3c 0.001) or chloroquine alone (P \u3c 0.05). All three SP-treated groups showed high and similar parasite reduction (0-48 hours), whereas treatment with chloroquine alone was much less effective. Levels of IgG antibodies to P. falciparum increased significantly (P \u3c 0.001) and similarly in the four treatment groups between days 0, 2. and 3. Thus, the addition of chloroquine or paracetamol to SP improved the clinical outcome, but did not affect the parasitologic response or antibody production

Higher IL-10 levels are associated with less effective clearance of Plasmodium falciparum parasites

The implications of high levels of the immune regulatory cytokine IL-10 in Plasmodium falciparum malaria are unclear. IL-10 may down-regulate pro-inflammatory responses and also exacerbate disease by inhibiting anti-parasitic immune functions. To study possible inhibiting effects on parasite clearance, IL-10 plasma levels were determined in 104 Tanzanian children, 1 to 4 years old, with acute uncomplicated P. falciparum malaria, and analysed for association with parasite densities during 3 days of anti-malarial treatment. Higher baseline IL-10 plasma levels were associated with statistically significantly higher parasite densities after 24, 48 and 72 h of treatment. These associations could not be explained by differences in initial parasitaemia, temperature, age, sex or type of treatment. Induction of high IL-10 production might be a direct or indirect mechanism whereby the parasite evades the immune response

The concordance between the volume hotspot and the grade hotspot: a 3-D reconstructive model using the pathology outputs from the PROMIS trial.

The rationale for directing targeted biopsy towards the centre of lesions has been questioned in light of prostate cancer grade heterogeneity. In this study, we assess the assumption that the maximum cancer Gleason grade (Gleason grade hotspot) lies within the maximum dimension (volume hotspot) of a prostate cancer lesion. 3-D histopathological models were reconstructed using the outputs of the 5-mm transperineal mapping (TPM) biopsies used as the reference test in the pilot phase of Prostate Mri Imaging Study (PROMIS), a paired validating cohort study investigating the performance of multi-parametric magnetic resonance imaging (MRI) against transrectal ultrasound (TRUS) biopsies. The prostate was fully sampled with 5 mm intervals; each core was separately labelled, inked and orientated in space to register 3-D cancer lesions location. The data from the histopathology results were used to create a 3-D interpolated reconstruction of each lesion and identify the spatial coordinates of the largest dimension (volume hot spot) and highest Gleason grade (Gleason grade hotspot) and assess their concordance. Ninety-four men, with median age 62 years (interquartile range, IQR= 58-68) and median PSA 6.5 ng ml(-1) (4.6-8.8), had a median of 80 (I69-89) cores each with a median of 4.5 positive cores (0-12). In the primary analysis, the prevalence of homogeneous lesions was 148 (76%; 95% confidence interval (CI) ±6.0%). In all, 184 (94±3.2%) lesions showed concordant hotspots and 11/47 (23±12.1%) of heterogeneous lesions showed discordant hotspots. The median 3-D distance between discordant hotspots was 12.8 mm (9.9-15.5). These figures remained stable on secondary analyses using alternative reconstructive assumptions. Limitations include a certain degree of error within reconstructed models. Guiding one biopsy needle to the maximum cancer diameter would lead to correct Gleason grade attribution in 94% of all lesions and 79% of heterogeneous ones if a true hit was obtained. Further correlation of histological lesions, their MRI appearance and the detectability of these hotspots on MRI will be undertaken once PROMIS results are released

A Cost-Utility Analysis of Prostate Cancer Screening in Australia

Background and Objectives: The Göteborg randomised population-based prostate cancer screening trial demonstrated that Prostate Specific Antigen (PSA) based screening reduces prostate cancer deaths compared with an age matched control group. Utilising the prostate cancer detection rates from this study we have investigated the clinical and cost-effectiveness of a similar PSA-based screening strategy for an Australian population of men aged 50-69 years. Methods: A decision model that incorporated Markov processes was developed from a health system perspective.The base case scenario compared a population-based screening programme with current opportunistic screening practices. Costs, utility values, treatment patterns and background mortality rates were derived from Australian data. All costs were adjusted to reflect July 2015 Australian dollars. An alternative scenario compared systematic with opportunistic screening but with optimisation of active surveillance (AS) uptake in both groups. A discount rate of 5% for costs and benefits was utilised. Univariate and probabilistic sensitivity analyses were performed to assess the effect of variable uncertainty on model outcomes. Results: Our model very closely replicated the number of deaths from both prostate cancer and background mortality in the Göteborg study. The incremental cost per quality-adjusted life-year (QALY) for PSA screening was $AU147,528. However, for years of life gained (LYGs) PSA based screening ($AU45,890/LYG) appeared more favourable. Our alternative scenario with optimised AS improved cost-utility to $AU45,881/QALY, with screening becoming cost-effective at a 92$AU50,000/QALY. It appears more cost-effective if LYGs are used as the relevant outcome, and is more cost effective than the established Australian breast cancer screening programme on this basis. Optimised utilisation of AS increases the cost-effectiveness of prostate cancer screening dramatically

Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia

This study aimed to estimate the extent of 'overdiagnosis' of prostate cancer attributable to prostate-specific antigen (PSA) testing in the Cambridge area between 1996 and 2002. Overdiagnosis was defined conceptually as detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Records of PSA tests in Addenbrookes Hospital were linked to prostate cancer registrations by NHS number. Differences in prostate cancer registration rates between those receiving and not receiving prediagnosis PSA tests were calculated. The proportion of men aged 40 years or over with a prediagnosis PSA test increased from 1.4 to 5.2% from 1996 to 2002. The rate of diagnosis of prostate cancer was 45% higher (rate ratios (RR) = 1.45, 95% confidence intervals (CI) 1.02-2.07) in men with a history of prediagnosis PSA testing. Assuming average lead times of 5 to 10 years, 40-64% of the PSA-detected cases were estimated to be overdiagnosed. In East Anglia, from 1996 to 2000, a 1.6% excess of cases was associated with PSA testing (around a quarter of the 5.3% excess incidence cases observed in East Anglia from 1996 to 2000). Further quantification of the overdiagnosis will result from continued surveillance and from linkage of incidence to testing in other hospitals

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10−5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10−8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05–2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema

PCA3 molecular urine assay for prostate cancer: association with pathologic features and impact of collection protocols

IntroductionPCA3 is a non-coding mRNA molecule that is overexpressed in prostate cancer. The purpose of this study is to evaluate the utility of the PCA3 molecular urine test scores to predict adverse pathologic features and catheterized specimen collection.MethodsHundred men with clinically localized prostate cancer scheduled to undergo robotic prostatectomy were enrolled in the study following a standard consent process. The study protocol consisted of providing four urine samples. Voided urine obtained following digital rectal examination (DRE) pre-operatively (Vl), catheterized urine without DRE (V2), and l0-day and 6-week postoperative voided (V3 and V4) urine samples were collected and analyzed. These four urine specimens underwent target capture, transcription-mediated amplification, and hybridization in order to quantify both PCA3 and PSA mRNA. The PCA3 score was calculated as the ratio of PCA3 to PSA.ResultsInformative rates (sufficient mRNA for analysis) for VI, V2, V3 and V4 were 91, 85, 0 and 2%, respectively. There was no significant associations with pathological stage, Gleason score &gt;6. Higher PCA3 scores at V1 correlated with increased risk for perineural invasion (P = 0.0479).ConclusionsInformative PCA3 scores can be obtained from post-DRE voided urine as well as catheterized urine without a DRE. The PCA3 test does not seem to predict adverse pathologic features, though, may have an association with perineural invasion. The ability of PCA3 score to predict clinical outcome remains to be determined

Men's preferences for prostate cancer screening: A discrete choice experiment

Background: Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. Methods: A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC-related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. Results: The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay \[euro]188 per year (CI: \[euro]141-\[euro]258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. Conclusion: Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening. © 2013 Cancer Research UK. All rights reserved

Treatment of local-regional prostate cancer detected by PSA screening: Benefits and harms according to prognostic factors

Background:Men with screen-detected prostate cancer can choose to undergo immediate curative treatment or enter into an expectant management programme. We quantified how the benefits and harms of immediate treatment vary according to the prognostic factors of clinical T-stage, Gleason score, and patient age.Methods:A microsimulation model based on European Randomized Study of Screening for Prostate Cancer data was used to predict the benefits and harms of immediate treatment versus delayed treatment of local-regional prostate cancer in men aged 55-74 years. Benefits included life-years gained and reduced probability of death from prostate cancer. Harms included lead time and probability of overdiagnosis.Results:The ratio of mean lead time to mean life-years gained ranged from 1.8 to 31.2, and the additional number of treatments required per prostate cancer death prevented ranged from 0.3 to 11.6 across the different prognostic groups. Both harm-benefit ratios were lowest, most favourable, for men aged 55-59 years and diagnosed with moderate-risk prostate cancer. Ratios were high for men aged 70-74 years regardless of clinical T-stage and Gleason score.Conclusion:Men aged 55-59 years with moderate-risk prostate cancer are predicted to derive greatest benefit from immediate curative treatment. Immediate treatment is least favourable for men aged 70-74 years with either low-risk or high-risk prostate cancer