Maternal thyroid hormone concentration during late gestation is associated with foetal position at birth

Objective  To evaluate whether there is an association between maternal thyroid hormone and foetal cephalic head position at term gestation.
Context  Rotation and flexion of the head enables the foetus to negotiate the birth canal. Low-normal range thyroid hormone concentrations in euthyroid pregnant women constitute a risk of infant motor abnormality. We hypothesized that low normal maternal thyroid hormone levels are associated with increased risk of abnormal foetal position at delivery.
Design  In 960 healthy Dutch women with term gestation and cephalic foetal presentation, thyroid parameters [foetal T4 (FT4), TSH and thyroid peroxidase antibody] were assessed at 36 weeks of gestation, and related to foetal head position (anterior cephalic vs. abnormal cephalic) and delivery mode (spontaneous vs. assisted delivery).
Results  Women presenting in anterior position ( n  = 891) had significantly higher FT4 levels at 36 weeks of gestation than those with abnormal cephalic presentation ( n  = 69). There were no between-group differences for TSH. Regression analyses indicated that the risk of abnormal head position decreased as a function of increasing FT4 [single odds ratio (OR) = 0·87, 95% confidence intervals (CI) 0·77–0·98; multivariate OR = 0·88, 95% CI 0·72–0·99)]. A similar inverse relationship between maternal FT4 and risk of assisted delivery was obtained (OR = 0·86, 95% CI 0·79–0·95; OR = 0·91, 95% CI 0·84–0·98).
Conclusion  The lower the maternal FT4 concentration at 36 weeks of gestation, the higher the risk of abnormal cephalic foetal presentation and assisted delivery.     

Common community acquired infections and subsequent risk of chronic lymphocytic leukaemia

Emerging evidence supports a role for immune-related factors in the causation of chronic lymphocytic leukaemia (CLL). Using the population-based U.S. Surveillance Epidemiology and End Results-Medicare database, 10 171 elderly CLL patients and 122 531 frequency-matched controls were identified in order to evaluate several community acquired infections associated with subsequent CLL risk. Odds ratios (ORs) were adjusted for gender, age, race, calendar year and number of physician claims. CLL risk was increased following Medicare claims for sinusitis (OR = 1·11; 95% CI = 1·05–1·17), pharyngitis (OR = 1·15; 1·08–1·22), bronchitis (OR = 1·14; 1·08–1·19), pneumonia (OR = 1·17; 1·11–1·24), influenza (OR = 1·10; 1·01–1·19), cellulitis (OR = 1·08; 1·02–1·14) and herpes zoster (OR = 1·26; 1·15–1·37). Associations with pneumonia and cellulitis remained significant when the 5-year period before diagnosis/control selection was excluded. CLL risk increased with increasing severity/frequency of pneumonia ( P  = 0·005), cellulitis ( P  < 0·001) and herpes zoster ( P  < 0·001). Our findings suggest that common infections may play a role in CLL aetiology. Alternatively, the associations might reflect an underlying immune disturbance present several years prior to CLL diagnosis.     

Risk of non-Hodgkin lymphoma in association with germline variation in complement genes

Germline mutations in complement genes have been associated with susceptibility to infections and autoimmune diseases, conditions that are associated with non-Hodgkin lymphoma (NHL) risk. To test the hypothesis that common genetic variation in complement genes affect risk of NHL, we genotyped 167 single nucleotide polymorphisms (SNPs) from 31 genes in 441 NHL cases and 475 controls. Principal components (PC) and haplotype analyses were used for gene-level tests of NHL risk, while individual SNPs were modelled as having a log-additive effect. In gene level PC analyses, C2 ( P =  0·023), C5 ( P =  0·0032) and C9 ( P =  0·020) were associated with NHL risk; haplotype analyses showed similar results, as well as a haplotype association for C7 ( P =  0·046). When all four genes were considered simultaneously, only C5 and C9 remained significant ( P <  0·05). In SNP level results from these genes, 10 SNPs had a P <  0·05. However, after correcting for multiple testing, only the C5 SNPs rs7026551 ( q  = 0·015; OR = 1·54, 95% CI 1·21–1·95) and rs2416810 ( q  = 0·015; OR = 1·57; 95% CI 1·22–2·01), and the C9 SNP rs187875 ( q  = 0·015; OR = 0·68; 95% 0·56–0·84) remained noteworthy. Associations were similar for the common NHL subtypes. In summary, we provide evidence for a role of genetic variation in complement genes, particularly C5 and C9 , and NHL risk.     

Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study

Prior case–control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged ≥45 years. A nested case–control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1·17[0·86–1·59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1·84[1·05–3·22]) and women (OR = 1·51[1·01–2·26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0·93[0·70–1·25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.     

Prior rituximab correlates with less acute graft-versus-host disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation

Prior therapy with rituximab might attenuate disparate histocompatibility antigen presentation by B cells, thus decreased the risk of acute graft-versus-host disease (GVHD) and improved survival. We tested this hypothesis by comparing the outcomes of 435 B-cell lymphoma patients who received allogeneic transplantation from 1999 to 2004 in the Center for International Blood and Marrow Transplant Research database: 179 subjects who received rituximab within 6 months prior to transplantation (RTX cohort) and 256 subjects who did not receive RTX within 6 months prior to transplantation (No-RTX cohort). The RTX cohort had a significantly lower incidence of treatment-related mortality (TRM) [relative risk (RR) = 0·68; 95% confidence interval (CI), 0·47–1·0; P  =   0·05], lower acute grade II–IV (RR = 0·72; 95% CI, 0·53–0·97; P  =   0·03) and III–IV GVHD (RR = 0·55; 95% CI, 0·34–0·91; P  =   0·02). There was no difference in the risk of chronic GVHD, disease progression or relapse. Progression-free survival (PFS) (RR = 0·68; 95% CI 0·50–0·92; P  =   0·01) and overall survival (OS) (RR = 0·63; 95% CI, 0·46–0·86; P  =   0·004) were significantly better in the RTX cohort. Prior RTX therapy correlated with less acute GVHD, similar chronic GVHD, less TRM, better PFS and OS.     

Naturally acquired immunoglobulin (Ig)G subclass antibodies to crude asexual Plasmodium falciparum lysates: evidence for association with protection for IgG1 and disease for IgG2

There is longstanding evidence for a role of immunoglobulin (Ig)G in protection against malarial disease and infection. IgG1 and IgG3 have been shown to be particularly efficient at associating with monocytes in potentially protective mechanisms (i.e. antibody-dependent cellular inhibition, opsonization and phagocytosis). Conversely, there is some evidence that IgG2 (and possibly IgG4) antibodies may be antagonistic to this protection. The protective effect of IgG subclass antibody activity present before the beginning of a malaria transmission season (preseason antibody levels) against severe malaria has not been tested in longitudinal studies. We measured IgG class and subclass antibody levels specific to crude Plasmodium falciparum lysates by enzyme linked immunosorbent assay in a case-control study of 76 children on the coast of Kenya. The mean optical density values for both IgG class and subclass antibodies were not significantly different between the children who developed severe malaria and those who remained healthy during an observation period of two malaria transmission seasons. However, elevated levels of IgG1 in relation to levels of IgG2 and IgG4 antibodies were associated with protection from severe malaria (P = 0.02). Conversely, elevated levels of IgG2 in relation to IgG1 and IgG3 antibodies were associated with a higher risk of developing severe malaria (P = 0.006).     

Use of supervised injection facilities and injection risk behaviours among young drug injectors

Aims   To study the use of supervised injection facilities (SIFs) as a predictor of safer injecting practices.
Design   Cross-sectional study conducted with face-to-face interview using a structured questionnaire with computer-assisted personal interviewing. Dried blood spot samples were collected for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) antibody testing.
Setting   All participants were street-recruited by chain referral methods in Madrid and Barcelona.
Participants   A total of 249 young heroin drug injectors recruited by the ITINERE cohort study in two Spanish cities with SIFs.
Measurements   The main outcome measures were self-reported injecting behaviours and SIFs attendance.
Results   SIF users were more marginalized socially than non-users. They were also more often regular injectors (weekly or more versus sporadic) [odds ratio (OR) = 4.9, 95% confidence interval (CI): 2.7–8.8], speedball users (OR = 2.5, 95% CI: 1.5–4.3) and anti-HCV-positive (OR = 3.1, 95% CI: 1.4–7.1). In the logistic regression analysis, using SIFs was associated independently with not borrowing used syringes (OR = 3.3, 95% CI: 1.4–7.7). However, no significant association was found between SIF use and not sharing injection equipment indirectly (OR = 1.1, 95% CI: 0.5–2.2).
Conclusions   SIFs attract highly disadvantaged drug injectors who engage none the less in less borrowing of used syringes than non-users of these facilities. The risks of indirect sharing should be emphasized when counselling SIF attendees.     

Performance of OptiMAL-IT® compared to microscopy, for malaria detection in Burkina Faso

Objective  To compare the performance of OptiMAL-IT^®, a rapid diagnostic test for malaria, with that of microscopy in Burkina Faso.
Method  Finger-prick blood samples of 464 children attending hospital for suspected malaria were tested for malaria by microscopy and OptiMAL-IT^®.
Results  The sensitivity and specificity of OptiMAL-IT^® were 98.7% (CI 95% = 97.6–99.8) and 96.2% (CI 95% = 94.3–98.1) respectively, with a high positive likelihood ratio (25.97).
Conclusion  OptiMAL-IT^® can be considered a good method to diagnose malaria in Burkina Faso, particularly in remote areas with little or no access to microscopy services.     

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease

Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sß⁰ thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) ≥2·5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19–31 months). Patients with initial TRV ≥ 3 or TRV ≥ 2·5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow-up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram ( P  = 0·01), lower haemoglobin ( P  = 0·003) and lower oxygen saturation ( P  = 0·03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40·16 to 29·26 ( P  = 0·017) after 3–6 months and to 23·6 mmHg ( P  = 0·002) after 9–12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea.     

Adherence to artesunate–amodiaquine combination therapy for uncomplicated malaria in children in Zanzibar, Tanzania

Objectives  To estimate caretaker adherence to co-blistered, but not co-formulated, artesunate-amodiaquine (AsAq) for uncomplicated malaria and identify factors associated with caretaker adherence.
Methods  Cross sectional household survey of caretakers of 210 children under 5 years of age who had been prescribed and dispensed AsAq at 21 public health facilities (HFs). The caretakers were interviewed in their homes on the 4th day of receiving the 3 day treatment. Adherence of caretakers was assessed by self report and pill count.
Results  Caretaker adherence to AsAq was 77% (95% CI: 67%–87%). Non-adherence resulted in under-dosing ¾ of the time and was most often in the form of wrong daily doses due to misunderstanding or forgetting the correct dose regimens. Predictors of adherence were education exceeding 7 years (OR = 5.08, P  = 0.008) and receiving the exact number of pills to complete the treatment regimen (OR = 4.09, P  = 0.006). All caretakers of children who were administered the first dose at the HF had adhered to the treatment.
Conclusion  We found moderate levels of caretaker adherence to AsAq. Further improvement could be achieved by producing dose-specific packaging for infants, providing clear instructions and giving the first dose under observation at the HF.     

Differential antibody responses to Plasmodium falciparum merozoite proteins in Malawian children with severe malaria

Cerebral malaria (CM) and severe malarial anemia (SMA) are 2 major causes of death in African children infected with Plasmodium falciparum. We investigated levels of naturally acquired antibody to conserved and variable regions of merozoite surface protein (MSP)-1 and MSP-2, apical membrane antigen (AMA)-1, and rhoptry-associated protein 1 in plasma samples from 126 children admitted to the hospital with CM, 59 with SMA, and 84 with uncomplicated malaria (UM) in Malawi. Children with SMA were distinguished by very low levels of immunoglobulin (Ig) G to the conserved C-terminus of MSP-1 and MSP-2 and to full-length AMA-1. Conversely, children with CM had significantly higher levels of IgG to the conserved regions of all antigens examined than did children with UM (for MSP-1 and AMA-1, P< .005; for MSP-2, P< .05) or SMA (for MSP-1 and MSP-2, P<.001; for AMA-1, P< .005). These distinct IgG patterns might reflect differences in age, exposure to P. falciparum, and/or genetic factors affecting immune responses.     

Cross-sectional survey of the extent and indicators of hepatitis C virus infection in Houston Department of Health and Human Services' sexually transmitted disease clinics

summary. To evaluate the prevalence and indicators of hepatitis C virus (HCV) infection in Houston and determine the effectiveness of targeted HCV screening in sexually transmitted disease (STD) clinics. We performed a cross-sectional survey in low-risk and high-risk groups in Houston. This included a blinded survey of HCV conducted in 1010 STD clinic clients having serological syphilis tests, and 1885 multi-speciality group practice patients having metabolic blood work. This was followed with a targeted hepatitis C survey of 822 high-risk clients from STD clinics. The seroprevalence of hepatitis C infection in the blinded survey was 3.9% (95% CI 3.0–4.8) in the multi-speciality group and 5.0% (95% CI 3.7–6.3) in the STD clinics. Prevalence of hepatitis C infection among targeted STD clinic clients was significantly higher at 15.3% (95% CI 12.7–17.7). Risk factors that correlated with HCV infection after logistic regression included: injection drug use (OR = 10, 95% CI =  3.4–30.3), heroin use (OR = 6.6, 95% CI = 2.2–20.5), non-transfusion/ transplantation blood exposure (OR = 3.0, 95% CI = 1.3–6.9), sharing equipment to snort drugs (OR = 2.5, 95% CI 1.2–5.4), and age above 25 years (OR = 51, 95% CI = 9–47). This study demonstrates that targeting clients in STD clinics for known risk behaviours is an effective way to identify cases of HCV infection. STD clinics allow access to clients with both drug use and sexual risk behaviours and are a useful location for targeting hepatitis C screening and prevention efforts.     

Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic loci controlling fetal haemoglobin

High levels of fetal haemoglobin (HbF) are protective in β-haemoglobinopathies. The proportion of erythrocytes containing HbF (F-cells, FC) was measured in healthy adults of African and Caucasian ancestry to assess the feasibility of localizing genes for the FC trait using admixture mapping. Participants were Afro-Caribbean (AC) blood donors and residents of a rural enclave with a history of recent German admixture (Afro-German, AG) recruited in Jamaica, and Caucasian Europeans recruited in Jamaica and the UK. FC levels were significantly different between groups ( P  <   0·001); the geometric mean FC level in the AC sample ( n  = 176) was 3·75% [95% confidence interval (CI) 3·36–4·18], AG sample ( n  = 631) was 2·77% (95% CI 2·63–2·92), and among Caucasians ( n  = 1099) was 3·26% (95% CI 3·13–3·39). After adjustment for age, sex, haemoglobin electrophoresis pattern, and HBG2 genotype, FC levels in the AC group remained significantly different ( P  <   0·001) from those in the Caucasian and the AG group but the difference between the Caucasian and AG groups became non-significant ( P  =   0·46) despite substantial differences in average ancestry. The data confirm ethnic differences in FC levels and indicate the potential usefulness of these populations for admixture mapping of genes for FC levels.     

Interleukin-6 (IL-6) –572C→G promoter polymorphism is associated with type 2 diabetes risk in Koreans

Objective  Increased levels of inflammatory markers, such as interleukin-6 ( IL -6), are associated with type 2 diabetes (T2DM). We investigated the association of IL-6 gene polymorphisms with T2DM and circulating levels of IL -6 in Koreans.
Subjects  A total of 1477 subjects with normal glucose tolerance and 476 T2DM patients were included.
Measurements  We examined IL-6 – 174G→C, –572C→G, –597G→A and –1363G→T promoter region polymorphisms. The main outcome measures were the odds ratio (OR) on T2DM risk and serum concentrations of IL -6 and high-sensitivity C-reactive protein (hs-CRP).
Results  Homozygosity for the rare G allele IL-6 – 572C→G was associated with a higher risk of T2DM [OR 1·69 (95%CI 1·11–2·58), P  = 0·015]. Serum IL -6 concentrations were associated with the IL-6 – 572C→G genotype in control subjects (G/G: 2·33 ± 0·41: C/G: 1·53 ± 0·09: C/C: 1·72 ± 0·08 ng/l, P  = 0·023). Also in the control group, subjects homozygous for the rare G allele showed significantly higher concentrations of hs-CRP than C/C and C/G carriers (G/G: 13·6 ± 2·9: C/G: 9·2 ± 0·6: C/C: 7·8 ± 0·4 mg/l, P  = 0·003). The C-allele at the IL-6 – 174 SNP was very rare (< 0·01) and –597G→A and –1363G→T were monomorphic in this population.
Conclusions  Our data demonstrate that the IL-6 – 572G/G genotype is associated with higher serum IL -6 and hs-CRP concentrations and with increased risk for T2DM.     

Thyroid function and the natural history of depression: findings from the Caerphilly Prospective Study (CaPS) and a meta-analysis

Objective   Low thyroid function has been associated with depression in clinical populations. We have examined whether thyroid function in the normal range is associated with minor psychiatric morbidity.
Design   Prospective cohort study of 2269 middle aged men (45–59 years) with thyroid function (total T₄ only, TSH unavailable) measured between 1979 and 1983 and with repeat measures of minor psychiatric morbidity (GHQ-30) over a mean of 12·3 years follow-up. We also undertook a systematic review and meta-analysis of population-based studies examining thyroid function and mood.
Results   There was a positive association between total T₄ and chronic psychiatric morbidity (odds ratio 1·21, 95% CI 1·02–1·43, P = 0·03), but this was consistent with chance after adjusting for social class, alcohol and smoking behaviours. The association with incident and recovery from psychiatric morbidity was weaker and consistent with chance.
We identified seven eligible studies, from our systematic review and included six studies, including our own, in a meta-analysis. The pooled estimate showed a positive association (odds ratio 1·12, 95% CI 1·02–1·22, P -value = 0·01) between depression and T₄ and an inverse association with TSH (odds ratio 0·92, 95% CI 0·88–0·97, P = 0·0007) with no evidence of heterogeneity or publication bias.
Conclusion   The results from CaPS and our meta-analysis are consistent and suggest that, if anything, higher levels of thyroxine in the normal range are associated with increased risk of depression. The effects of thyroid hormone on mood may differ in normal populations and patients with clinical thyroid dysfunction.     

Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis

Aims   To assess the effectiveness of current treatment approaches to assist benzodiazepine discontinuation.
Methods   A systematic review of approaches to benzodiazepine discontinuation in general practice and out-patient settings was undertaken. Routine care was compared with three treatment approaches: brief interventions, gradual dose reduction (GDR) and psychological interventions. GDR was compared with GDR plus psychological interventions or substitutive pharmacotherapies.
Results   Inclusion criteria were met by 24 studies, and a further eight were identified by future search. GDR [odds ratio (OR) = 5.96, confidence interval (CI) = 2.08–17.11] and brief interventions (OR = 4.37, CI = 2.28–8.40) provided superior cessation rates at post-treatment to routine care. Psychological treatment plus GDR were superior to both routine care (OR = 3.38, CI = 1.86–6.12) and GDR alone (OR = 1.82, CI = 1.25–2.67). However, substitutive pharmacotherapies did not add to the impact of GDR (OR = 1.30, CI = 0.97–1.73), and abrupt substitution of benzodiazepines by other pharmacotherapy was less effective than GDR alone (OR = 0.30, CI = 0.14–0.64). Few studies on any technique had significantly greater benzodiazepine discontinuation than controls at follow-up.
Conclusions   Providing an intervention is more effective than routine care. Psychological interventions may improve discontinuation above GDR alone. While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.     

Interleukin-10–592C/A, –819C/T and –1082A/G promoter variants affect the susceptibility to nephropathy in Tunisian type 2 diabetes (T2DM) patients

Background  The Interleukin (IL)-10 polymorphic variants –1082G/A, –819C/T and –592C/A were linked with obesity, metabolic syndrome, and type 2 diabetes (T2DM). We investigated the hypothesis that IL-10 promoter polymorphisms may be associated with the progression of diabetic nephropathy (DN).
Design  Case-controlled study.
Patients  Study subjects comprised of 515 DN patients, and 402 normoalbuminuric (DWN) T2DM patients.
Measurements  IL-10 genotyping was done by PCR-based assays, and the contributions of the IL-10 polymorphic variants to DN were analysed by haplotype analysis and multivariate regression analysis.
Results  Decreased prevalence of (mutant) –819T allele and –819C/T genotype was seen in DN patients; neither the –1082G/A nor the –592C/A polymorphism was associated with DN. Three-loci haplotype (–1082GA/–819CT/–592CA) analysis identified GTC as DN-protective haplotype. Multivariate regression analysis confirmed the association of GTC haplotype ( P =  0·045; O R  = 0·56, 95% CI: 0·31–0·99), and in addition identified GTA haplotype ( P =  0·044; O R  = 0·54, 95% CI: 0·30–0·98) as independent predictors of DN after controlling for a number of covariates (age, sex, BMI; hypertension, glucose, HbA1c, DN duration, total cholesterol, medications).
Conclusion  This study suggests that IL-10 promoter polymorphism influence the risk of nephropathy in Tunisian T2DM patients.     

Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993

The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone-specific immunoglobulin or T-cell Receptor rearrangements was analysed in 161 patients with non T-lineage Philadelphia-negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (≥10⁻⁴) in patients treated with chemotherapy alone was associated with significantly shorter relapse-free survival (RFS) at several time-points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8·95 (2·85–28·09)-fold higher in MRD-positive (≥10⁻⁴) patients and the 5-year RFS 15% [95% confidence interval (CI) 0–40%] compared to 71% (56–85%) in MRD-negative (<10⁻⁴) patients ( P  = 0·0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5-year RFS 25% (CI 0–55%) vs. 77% (95% CI 54–100%) in MRD-negative/<10⁻⁴, P  = 0·01] whereas in recipients of allogeneic-SCT in first complete remission, MRD positivity pre-transplant did not adversely affect outcome. These data provide a rationale for introducing MRD-based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.     

Familial aggregation of cerebral malaria and severe malarial anemia

BACKGROUND: The predominant manifestations of severe malaria in African children are cerebral malaria (CM) and severe malarial anemia (SMA). As a first step toward a family-based approach to identify the environmental and genetic pathways that contribute to severe malaria, we tested whether it aggregates within families. METHODS: Family history of severe malaria was explored during face-to-face interviews with parents. Logistic regression was used to determine whether CM and SMA aggregate within individuals and within families. The pattern of familial aggregation was then expressed as familial odds ratios that were adjusted for relevant risk factors. RESULTS: This study was of 2811 inhabitants of Bamako, Mali, clustered in 407 nuclear families. The probands were 136 children with severe malaria and 271 healthy children from the community. Within-person association of CM and SMA was significant (odds ratio, 6.15 [95% confidence interval (CI), 2.62-14.41]). Over a lifetime, with each additional affected relative, the odds of a person contracting CM increased by 1.98 times (95% CI, 1.59-2.45), and the odds of having SMA increased by 1.91 times (95% CI, 1.05-3.47). Over a lifetime, for a child whose sibling had a history of CM, the odds of having CM were 2.49 times greater (95% CI, 1.51-4.10) than the odds for a child whose sibling had no such history; for a child whose sibling had a history of SMA, the odds of having SMA were 4.92 times greater (95% CI, 1.21-19.9) than the odds for a child whose sibling had no such history. CONCLUSION: Our data suggest strong familial aggregation of CM and SMA.     

Do antibody responses to malaria vaccine candidates influenced by the level of malaria transmission protect from malaria?

Objectives To examine whether the humoural response to malaria vaccine candidate antigens, Plasmodium falciparum [circumsporozoite repetitive sequence (NANP)₅ GLURP fragments (R0 and R2) and MSP3] varies with the level of malaria transmission and to determine whether the antibodies (IgG) present at the beginning of the malaria transmission season protect against clinical malaria. Methods Cross‐sectional surveys were conducted to measure antibody response before, at the peak and at the end of the transmission season in children aged 6 months to 10 years in two villages with different levels of malaria transmission. A cohort study was performed to estimate the incidence of clinical malaria. Results Antibodies to these antigens showed different seasonal patterns. IgG concentrations to any of the four antigens were higher in the village with high entomological inoculation rate. Multivariate analysis of combined data from the two villages indicated that children who were classified as responders to the selected antigens were at lower risk of clinical malaria than children classified as non‐responders [(NANP)₅ (incidence rate ratio (IRR) = 0.65, 95% CI: 0.46–0.92; P = 0.016), R0 (IRR = 0.69, 95% CI: 0.48–0.97; P = 0.032), R2 (IRR = 0.73, 95% CI: 0.50–1.06; P = 0.09), MSP3 (IRR = 0.52, 95% CI: 0.32–0.85; P = 0.009)]. Fitting a model with all four antibody responses showed that MSP3 looked the best malaria vaccine candidate (IRR = 0.63; 95% CI: 0.38–1.05; P = 0.08). Conclusion Antibody levels to the four antigens are affected by the intensity of malaria transmission and associated with protection against clinical malaria. It is worthwhile investing in the development of these antigens as potential malaria vaccine candidates.