Showing papers by "Mahidol University published in 2011"

Effect of nesiritide in patients with acute decompensated heart failure.

Abstract: A b s t r ac t Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.)

Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Abstract: With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m 2 . Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥1.0 mg/liter.

Determinants of relapse periodicity in Plasmodium vivax malaria.

Abstract: Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

Spread of methicillin-resistant Staphylococcus aureus between the community and the hospitals in Asian countries: an ANSORP study

Abstract: Objectives Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals in many Asian countries. Recent emergence of community-associated (CA) MRSA worldwide has added another serious concern to the epidemiology of S. aureus infections. To understand the changing epidemiology of S. aureus infections in Asian countries, we performed a prospective, multinational surveillance study with molecular typing analysis. Methods We evaluated the prevalence of methicillin resistance in S. aureus isolates in CA and healthcare-associated (HA) infections, and performed molecular characterization and antimicrobial susceptibility tests of MRSA isolates. Results MRSA accounted for 25.5% of CA S. aureus infections and 67.4% of HA infections. Predominant clones of CA-MRSA isolates were ST59-MRSA-SCCmec type IV-spa type t437, ST30-MRSA-SCCmec type IV-spa type t019 and ST72-MRSA-SCCmec type IV-spa type t324. Previously established nosocomial MRSA strains including sequence type (ST) 239 and ST5 clones were found among CA-MRSA isolates from patients without any risk factors for HA-MRSA infection. CA-MRSA clones such as ST59, ST30 and ST72 were also isolated from patients with HA infections. Conclusions Our findings confirmed that MRSA infections in the community have been increasing in Asian countries. Data also suggest that various MRSA clones have spread between the community and hospitals as well as between countries.

Role of the Acetabular Labrum and the Iliofemoral Ligament in Hip Stability: An in vitro Biplane Fluoroscopy Study

Abstract: BackgroundRecent biomechanical reports have described the function of the acetabular labrum and iliofemoral ligament in providing hip stability, but the relative stability provided by each structure has not been well described.HypothesisBoth the iliofemoral ligament and acetabular labrum are important for hip stability by limiting external rotation and anterior translation, with increased stability provided by the iliofemoral ligament compared with the acetabular labrum.Study DesignControlled laboratory study.MethodsFifteen fresh-frozen male cadaveric hips were utilized for this study. Each specimen was selectively skeletonized down to the hip capsule. Four tantalum beads were embedded into each femur and pelvis to accurately measure hip translations and rotations using biplane fluoroscopy while either a standardized 5 N·m external or internal rotation torque was applied. The hips were tested in 4 hip flexion angles (10° of extension, neutral, and 10° and 40° of flexion) in the intact state and then by se...

End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age

Abstract: Previous analyses from a randomised trial in women aged 24–45 years have shown the quadrivalent human papillomavirus (qHPV) vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN), and external genital lesions (EGLs) related to HPV 6/11/16/18. In this report, we present end-of-study efficacy, safety, and immunogenicity data with a median follow-up time of 4.0 years. We enrolled 3819 24–45-year-old women with no history of cervical disease or genital warts in the past 5 years. Women received quadrivalent vaccine or placebo at day 1, and at months 2 and 6. Ascertainment of CIN/EGL was accomplished through Pap testing, genital inspection, and cervicovaginal sampling (every 6 months). The main analysis was conducted in a per-protocol efficacy population (that received three doses, was naive to the relevant HPV types at day 1, and remained free of infection through month 7). Efficacy was also estimated in other naive and non-naive populations. Vaccine efficacy against the combined incidence of persistent infection, CIN/EGL related to HPV6/11/16/18 in the per-protocol population was 88.7% (95% CI: 78.1, 94.8). Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9% (95% CI: 4.3, 90.6). At month 48, 91.5, 92.0, 97.4, and 47.9% of vaccinated women were seropositive to HPV 6/11/16/18, respectively. No serious vaccine-related adverse experiences were reported. The qHPV vaccine demonstrated high efficacy, immunogenicity, and acceptable safety in women aged 24–45 years, regardless of previous exposure to HPV vaccine type.

High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia.

Abstract: Rationale: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain important causes of morbidity and mortality. Increasing antimicrobial resistance has aroused the concern of the failure of antibiotic treatment.Objectives: To determine the distribution of the bacterial isolates of HAP and VAP, their antimicrobial resistance patterns, and impact of discordant antibiotic therapy on clinical outcome in Asian countriesMethods: A prospective surveillance study was conducted in 73 hospitals in 10 Asian countries from 2008–2009. A total of 2,554 cases with HAP or VAP in adults were enrolled and 2,445 bacterial isolates were collected from 1,897 cases. Clinical characteristics and antimicrobial resistance profiles were analyzed.Measurement and Main Results: Major bacterial isolates from HAP and VAP cases in Asian countries were Acinetobacter spp., Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. Imipenem resistance rates of Acinetobacter and P. aeruginosa were 6...

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Abstract: Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

The Threat of Artemisinin-Resistant Malaria

Abstract: Since the 1970s, when Chinese researchers demonstrated the artemisinins' antimalarial potency, artemisinin-based combination therapy has become key to malaria control. But reduced susceptibility of Plasmodium falciparum to artemisinin is now being seen in some places.

Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator

Abstract: Background A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia. Accurate measurement of parasite clearance is therefore essential to assess the spread of artemisinin resistance in Plasmodium falciparum. The slope of the log-parasitaemia versus time relationship is considered to be the most robust measure of anti-malarial effect. However, an initial lag phase of numerical instability often precedes a steady exponential decline in the parasite count after the start of anti-malarial treatment. This lag complicates the clearance estimation, introduces observer subjectivity, and may influence the accuracy and consistency of reported results.

The cluster 1 type VI secretion system is a major virulence determinant in Burkholderia pseudomallei.

Abstract: The Burkholderia pseudomallei K96243 genome encodes six type VI secretion systems (T6SSs), but little is known about the role of these systems in the biology of B. pseudomallei. In this study, we purified recombinant Hcp proteins from each T6SS and tested them as vaccine candidates in the BALB/c mouse model of melioidosis. Recombinant Hcp2 protected 80% of mice against a lethal challenge with K96243, while recombinant Hcp1, Hcp3, and Hcp6 protected 50% of mice against challenge. Hcp6 was the only Hcp constitutively produced by B. pseudomallei in vitro; however, it was not exported to the extracellular milieu. Hcp1, on the other hand, was produced and exported in vitro when the VirAG two-component regulatory system was overexpressed in trans. We also constructed six hcp deletion mutants (Δhcp1 through Δhcp6) and tested them for virulence in the Syrian hamster model of infection. The 50% lethal doses (LD(50)s) for the Δhcp2 through Δhcp6 mutants were indistinguishable from K96243 ( 10(3) bacteria. The hcp1 deletion mutant also exhibited a growth defect in RAW 264.7 macrophages and was unable to form multinucleated giant cells in this cell line. Unlike K96243, the Δhcp1 mutant was only weakly cytotoxic to RAW 264.7 macrophages 18 h after infection. The results suggest that the cluster 1 T6SS is essential for virulence and plays an important role in the intracellular lifestyle of B. pseudomallei.

Melioidosis: a clinical overview

Abstract: Introduction: melioidosis, an infection caused by the environmental Gramnegative bacillus Burkholderia pseudomallei, has emerged as an important cause of morbidity and mortality in Southeast Asia and northern Australia. Sources of data: a review of the literature using PubMed. Areas of agreement: approaches to diagnosis and antimicrobial therapy. Areas of controversy: whether seroconversion signals the presence of a quiescent bacterial focus and an increase in long-term risk of melioidosis. Areas timely for developing research: melioidosis is potentially preventable, but there is a striking lack of evidence on which to base an effective prevention programme. An accurate map defining the global distribution of B. pseudomallei is needed, together with studies on the relative importance of different routes of infection. There is a marked difference in mortality from melioidosis in high-income versus lower income countries, and affordable strategies that reduce death from severe sepsis (from any cause) in resourcerestricted settings are needed.

The oncologic outcome and immediate surgical complications of lipofilling in breast cancer patients: a multicenter study--Milan-Paris-Lyon experience of 646 lipofilling procedures.

Abstract: Background:Lipofilling is now performed to improve the breast contour, after both breast-conserving surgery and breast reconstruction. However, injection of fat into a previous tumor site may create a new environment for cancer and adjacent cells. There is also no international agreement regarding l

A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study

Abstract: Background: Patients with chest pain contribute substantially to emergency department attendances, lengthy hospital stay, and inpatient admissions. A reliable, reproducible, and fast process to identify patients presenting with chest pain who have a low short-term risk of a major adverse cardiac event is needed to facilitate early discharge. We aimed to prospectively validate the safety of a predefined 2-h accelerated diagnostic protocol (ADP) to assess patients presenting to the emergency department with chest pain symptoms suggestive of acute coronary syndrome. Methods: This observational study was undertaken in 14 emergency departments in nine countries in the Asia-Pacific region, in patients aged 18 years and older with at least 5 min of chest pain. The ADP included use of a structured pre-test probability scoring method (Thrombolysis in Myocardial Infarction [TIMI] score), electrocardiograph, and point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin. The primary endpoint was major adverse cardiac events within 30 days after initial presentation (including initial hospital attendance). This trial is registered with the Australia-New Zealand Clinical Trials Registry, number ACTRN12609000283279. Findings: 3582 consecutive patients were recruited and completed 30-day follow-up. 421 (11•8%) patients had a major adverse cardiac event. The ADP classified 352 (9•8%) patients as low risk and potentially suitable for early discharge. A major adverse cardiac event occurred in three (0•9%) of these patients, giving the ADP a sensitivity of 99•3% (95% CI 97•9–99•8), a negative predictive value of 99•1% (97•3–99•8), and a specificity of 11•0% (10•0–12•2). Interpretation: This novel ADP identifies patients at very low risk of a short-term major adverse cardiac event who might be suitable for early discharge. Such an approach could be used to decrease the overall observation periods and admissions for chest pain. The components needed for the implementation of this strategy are widely available. The ADP has the potential to affect health-service delivery worldwide.

Management of Chronic Prostatitis/ Chronic Pelvic Pain Syndrome: A Systematic Review and Network Meta-analysis

Abstract: Context Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is common, but trial evidence is conflicting and therapeutic options are controversial. Objective To conduct a systematic review and network meta-analysis comparing mean symptom scores and treatment response among α-blockers, antibiotics, anti-inflammatory drugs, other active drugs (phytotherapy, glycosaminoglycans, finasteride, and neuromodulators), and placebo. Data Sources We searched MEDLINE from 1949 and EMBASE from 1974 to November 16, 2010, using the PubMed and Ovid search engines. Study Selection Randomized controlled trials comparing drug treatments in CP/CPPS patients. Data Extraction Two reviewers independently extracted mean symptom scores, quality-of-life measures, and response to treatment between treatment groups. Standardized mean difference and random-effects methods were applied for pooling continuous and dichotomous outcomes, respectively. A longitudinal mixed regression model was used for network meta-analysis to indirectly compare treatment effects. Data Synthesis Twenty-three of 262 studies identified were eligible. Compared with placebo, α-blockers were associated with significant improvement in symptoms with standardized mean differences in total symptom, pain, voiding, and quality-of-life scores of −1.7 (95% confidence interval [CI], −2.8 to −0.6), −1.1 (95% CI, −1.8 to −0.3), −1.4 (95% CI, −2.3 to −0.5), and −1.0 (95% CI, −1.8 to −0.2), respectively. Patients receiving α-blockers or anti-inflammatory medications had a higher chance of favorable response compared with placebo, with pooled RRs of 1.6 (95% CI, 1.1-2.3) and 1.8 (95% CI, 1.2-2.6), respectively. Contour-enhanced funnel plots suggested the presence of publication bias for smaller studies of α-blocker therapies. The network meta-analysis suggested benefits of antibiotics in decreasing total symptom scores (−9.8; 95% CI, −15.1 to −4.6), pain scores (−4.4; 95% CI, −7.0 to −1.9), voiding scores (−2.8; 95% CI, −4.1 to −1.6), and quality-of-life scores (−1.9; 95% CI, −3.6 to −0.2) compared with placebo. Combining α-blockers and antibiotics yielded the greatest benefits compared with placebo, with corresponding decreases of −13.8 (95% CI, −17.5 to −10.2) for total symptom scores, −5.7 (95% CI, −7.8 to −3.6) for pain scores, −3.7 (95% CI, −5.2 to −2.1) for voiding, and −2.8 (95% CI, −4.7 to −0.9) for quality-of-life scores. Conclusions α-Blockers, antibiotics, and combinations of these therapies appear to achieve the greatest improvement in clinical symptom scores compared with placebo. Anti-inflammatory therapies have a lesser but measurable benefit on selected outcomes. However, beneficial effects of α-blockers may be overestimated because of publication bias.

An In-Depth Analysis of Original Antigenic Sin in Dengue Virus Infection

Abstract: The evolution of dengue viruses has resulted in four antigenically similar yet distinct serotypes. Infection with one serotype likely elicits lifelong immunity to that serotype, but generally not against the other three. Secondary or sequential infections are common, as multiple viral serotypes frequently cocirculate. Dengue infection, although frequently mild, can lead to dengue hemorrhagic fever (DHF) which can be life threatening. DHF is more common in secondary dengue infections, implying a role for the adaptive immune response in the disease. There is currently much effort toward the design and implementation of a dengue vaccine but these efforts are made more difficult by the challenge of inducing durable neutralizing immunity to all four viruses. Domain 3 of the dengue virus envelope protein (ED3) has been suggested as one such candidate because it contains neutralizing epitopes and it was originally thought that relatively few cross-reactive antibodies are directed to this domain. In this study, we performed a detailed analysis of the anti-ED3 response in a cohort of patients suffering either primary or secondary dengue infections. The results show dramatic evidence of original antigenic sin in secondary infections both in terms of binding and enhancement activity. This has important implications for dengue vaccine design because heterologous boosting is likely to maintain the immunological footprint of the first vaccination. On the basis of these findings, we propose a simple in vitro enzyme-linked immunosorbent assay (ELISA) to diagnose the original dengue infection in secondary dengue cases.

Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1

Abstract: Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P(meta) = 4.41 × 10(-11), per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P(meta) = 3.08 × 10(-10), per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.

Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

Abstract: Background Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates.

Gi/o Protein-Dependent and -Independent Actions of Pertussis Toxin (PTX)

Abstract: Pertussis toxin (PTX) is a typical A-B toxin. The A-protomer (S1 subunit) exhibits ADP-ribosyltransferase activity. The B-oligomer consists of four subunits (S2 to S5) and binds extracellular molecules that allow the toxin to enter the cells. The A-protomer ADP-ribosylates the α subunits of heterotrimeric Gi/o proteins, resulting in the receptors being uncoupled from the Gi/o proteins. The B-oligomer binds proteins expressed on the cell surface, such as Toll-like receptor 4, and activates an intracellular signal transduction cascade. Thus, PTX modifies cellular responses by at least two different signaling pathways; ADP-ribosylation of the Gαi/o proteins by the A-protomer (Gi/o protein-dependent action) and the interaction of the B-oligomer with cell surface proteins (Gi/o protein-independent action).

Haemoglobinopathies in Southeast Asia

Abstract: In Southeast Asia α-thalassaemia, β-thalassaemia, haemoglobin (Hb) E and Hb Constant Spring (CS) are prevalent. The abnormal genes in different combinations lead to over 60 different thalassaemia syndromes, making Southeast Asia the locality with the most complex thalassaemia genotypes. The four major thalassaemic diseases are Hb Bart's hydrops fetalis (homozygous α-thalassaemia 1), homozygous β-thalassaemia, β-thalassaemia/Hb E and Hb H diseases. α-Thalassaemia, most often, occurs from gene deletions whereas point mutations and small deletions or insertions in the β-globin gene sequence are the major molecular defects responsible for most β-thalassaemias. Clinical manifestations of α-thalassaemia range from asymptomatic cases with normal findings to the totally lethal Hb Bart's hydrops fetalis syndrome. Homozygosity of β-thalassaemia results in a severe thalassaemic disease while the patients with compound heterozygosity, β-thalassaemia/Hb E, present variable severity of anaemia, and some can be as severe as homozygous β-thalassaemia. Concomitant inheritance of α-thalassaemia and increased production of Hb F are responsible for mild clinical phenotypes in some patients. However, there are still some unknown factors that can modulate disease severity in both α- and β-thalassaemias. Therefore, it is possible to set a strategy for prevention and control of thalassaemia, which includes population screening for heterozygotes, genetic counselling and foetal diagnosis with selective abortion of affected pregnancies.

Impact of guidelines and enhanced antibiotic stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection

Abstract: Methods: This was a retrospective, quasi-experimental study using interrupted time series (ITS) over 12 months before and after the intervention. The setting was adult medical and surgical wards in University Hospital Lewisham, an acute general hospital in London. The intervention was introduced in April 2006. Revised guidelines avoided broad-spectrum antibiotics, e.g. fluoroquinolones, cephalosporins, clindamycin, amoxicillin and co-amoxiclav, as they were considered to be ‘high risk’ for CDI. Instead, ‘low risk’ antibiotics such as penicillin, clarithromycin, doxycycline, gentamicin, vancomycin, trimethoprim and nitrofurantoin were recommended. Changes in antibiotic usage and incidence of CDI before and after the intervention were compared using segmented regression analysis. The negative binomial model was used to analyse the time series to estimate the CDI incidence rate ratio (IRR) following the intervention. Results: The intervention was associated with a significant reduction in the use of fluoroquinolones by 105.33 defined daily doses (DDDs)/1000 occupied bed-days (OBDs) per month [95% confidence interval (CI) 34.18 –176.48, P,0.001] and cephalosporins by 45.93 DDDs/1000 OBDs/month (95% CI 24.11 –67.74, P,0.0001). There was no significant change in total antibiotic, clindamycin, amoxicillin or co-amoxiclav use. There was a significant decrease in CDI following the intervention [IRR 0.34 (0.20 –0.58), P, 0.0001]. Conclusions: Revised antibiotic guidelines and enhanced stewardship was associated with a significant stepwise reduction in the use of cephalosporins and fluoroquinolones and a significant decrease in the incidence of CDI.

The parasite clearance curve.

Abstract: Parasite clearance rates are important measures of anti-malarial drug efficacy. They are particularly important in the assessment of artemisinin resistance. The slope of the log-linear segment in the middle of the parasite clearance curve has the least inter-individual variance and is the focus of therapeutic assessment. The factors affecting parasite clearance are reviewed. Methods of presentation and the approaches to analysis are discussed.

Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation

Abstract: The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a complement regulatory plasma protein that attenuates the classical and lectin pathways. Soluble NS1 recruited C4BP to inactivate C4b in solution and on the plasma membrane. Mapping studies revealed that the interaction sites of NS1 on C4BP partially overlap with the C4b binding sites. Together, these studies further define the immune evasion potential of NS1 in reducing the functional capacity of C4 in complement activation and control of flavivirus infection.

Intrahost modeling of artemisinin resistance in Plasmodium falciparum

Abstract: Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic–pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03–0.67 in log10 scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration–effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.