The genetic architecture of dewlap pattern in Hispaniola anoles (Anolis distichus).

Color and pattern are often critical to survival and fitness, but we know little about their genetic architecture and heritability in groups like reptiles. We investigated the genetic architecture for the pattern of the dewlap-an extensible throat fan important for communication-in anole lizards. We studied the Hispaniolan bark anole (Anolis distichus)-a species that exhibits impressive intraspecific dewlap polymorphism across its range-by conducting multigenerational experimental crosses with 2 populations, one with a solid pale yellow dewlap and another with an orange dewlap surrounded by a yellow margin. Upon rejecting the hypothesis that the extent of the orange pattern is a quantitative trait resulting from many loci of minor effect, we used a maximum likelihood model-fitting framework to show that it is better explained as a simple Mendelian trait, with the solid yellow morph being dominant over the blush orange. The relatively simple genetic architecture underlying this important trait helps explain the complex distribution of dewlap color variation across the range of A. distichus and suggests that changes in dewlap color and pattern may evolve rapidly in response to natural selection.

Effects of Integrated Vector Management in the Control of Malaria Infection: An Intervention Study in a Malaria Endemic Community in Nigeria.

BACKGROUND/AIM: Malaria is a vector borne disease with high morbidity and mortality in endemic regions. In view to eliminating the disease, integrated vector and environmental hygiene practices have been advocated. There is paucity of studies on the effect of vector control measures on asymptomatic malaria infection which has been observed to be a reflection of malaria transmission. METHODS: Longitudinal community-based intervention study carried out from October to December 2017. Study participants were 477 individuals living in 100 households selected by snow-balling sampling methods. Pre-intervention period included training of all heads of households on vector control methods. During the intervention period, each household received waste bins, two long lasting insecticide bed nets and had wire screen on their doors and windows; every household member was screened for malaria (antigen) using the pf rapid diagnostic test kits. Each household were monitored to ensure they comply with the environmental hygiene practices they were taught. Post-intervention malaria infection was obtained at 8 week being end of the intervention period. RESULTS: Of the 100 households selected, 54.0% were from the lower social class, 45.0% middle class and only 1.0% upper class. Mean age [±] of the heads of the households was 37.1 ± 11.0 (range 16-68) years. There were 477 individuals recruited in the study from the 100 households; 234 (49.0%) females and 243 (51.0%) males; median age was 20.0 (range 1-100) years. Prevalence of malaria infection using mRDT during pre-intervention was 16.8% and an incidence of 1.3% post-intervention. There was 92.0% reduction in asymptomatic malaria infection showing marked reduction in malaria transmission in the study locale. CONCLUSION: Some integrated vector control measures such as use of insecticide-treated net and sanitation were found effective methods for reducing malaria infection and transmission in endemic region.

CONTEXTE/OBJECTIF: Le paludisme est une maladie à transmission vectorielle avec une morbidité et une mortalité élevées dans les régions endémiques. En vue d'éliminer la maladie, des pratiques d'hygiène intégrée des vecteurs et de l'environnement ont été préconisées. Il existe peu d'études sur l'effet des mesures de lutte antivectorielle sur l'infection palustre asymptomatique, qui s'est avérée être le reflet de la transmission du paludisme. MÉTHODES: Étude longitudinale d'intervention communautaire réalisée d'octobre à décembre 2017. Les participants à l'étude étaient 477 personnes vivant dans 100 ménages sélectionnés par des méthodes d'échantillonnage en boule de neige. La période de pré-intervention comprenait la formation de tous les chefs de ménage sur les méthodes de lutte antivectorielle. Au cours de la période d'intervention, chaque ménage a reçu des poubelles, deux moustiquaires à insecticide longue durée et avait des grillages sur leurs portes et fenêtres ; chaque membre du ménage a été dépisté pour le paludisme (antigène) à l'aide des kits de test de diagnostic rapide pf. Chaque ménage a été suivi pour s'assurer qu'il respecte les pratiques d'hygiène environnementale qui lui ont été enseignées. L'infection antipaludique post-intervention a été obtenue à 8 semaines, fin de la période d'intervention. RÉSULTATS: Sur les 100 ménages sélectionnés, 54,0% appartenaient à la classe sociale inférieure, 45,0% à la classe moyenne et seulement 1,0% à la classe supérieure. L'âge moyen [±] des chefs de ménage était de 37,1 ± 11,0 (fourchette de 16 à 68) ans. Il y avait 477 personnes recrutées dans l'étude à partir des 100 ménages ; 234 (49,0 %) femmes et 243 (51,0 %) hommes ; l'âge médian était de 20,0 (intervalle de 1 à 100) ans. La prévalence de l'infection du paludisme à l'aide de mRDT pendant la pré-intervention était de 16,8 % et l'incidence de 1,3 % après l'intervention. Il y avait une réduction de 92,0 % de l'infection asymptomatique du paludisme, montrant une réduction marquée de la transmission du paludisme dans le lieu de l'étude. CONCLUSION: Certaines mesures intégrées de lutte antivectorielle telles que l'utilisation de moustiquaires imprégnées d'insecticide et l'assainissement se sont révélées être des méthodes efficaces pour réduire l'infection et la transmission du paludisme dans les régions endémiques. Mots clés: Endémique, Hygiène Environnementale, Ménages, Intervention, Paludisme, Transmission, Vecteur.

Refractive Error and Visual Impairment Among School Children: Result of a South-Eastern Nigerian Regional Survey.

PURPOSE: To determine the prevalence refractive errors and causes of visual impairment in school children in the south-eastern region of Nigeria. METHODS: School-based cross-sectional samples of children 5 to 15 of age in both urban and rural areas were profiled through cluster sampling. The main outcome measures were presenting, uncorrected, and best-corrected visual acuity using the Refractive Error in School-age Children (RESC) protocol. RESULTS: A total of 5723 children were examined during the study period comprising 2686 (46.9%) males and 3037 (53.1%) females; (M:F ratio 0.9:1) and aged 10.49±2.74SD of mean (range, 5 to 15 years). The age group 12 to <13 accounted for the highest 776 (13.6%) number of the study participants. The uncorrected visual acuity (VA) of <20/40 (6/12) was seen in 188 (3.4%) of the study participants while the presenting and best-corrected visual acuity of <20/40 (6/12) were noted in 182 (3.4%) children and 14 (0.2%) children, respectively. Refractive error was the principal cause of visual impairment. CONCLUSION: Prevalence of refractive error is low. Myopia is the principal cause of refractive error occurring more in females and in urban schools. The main cause of visual impairment is refractive error, and most children that need spectacle correction did not have them. Program to identify children with refractive error in addition to providing free or affordable optical services remains the key to preventing visual impairment from refractive error particularly in resource-poor settings.

'Codeine is my companion': misuse and dependence on codeine containing medicines in Ireland.

OBJECTIVES: Global concern around over the counter availability of codeine containing products and risk of misuse, dependence and related harms are evident. A phenomenological study of lived experiences of codeine misuse and dependence was undertaken in Ireland, following the Pharmaceutical Society of Ireland's 2010 guidelines for restricted supply of non-prescription codeine containing products. METHODS: In-depth interviews were conducted with a purposive sample of adult codeine misusers and dependents (n=21), both actively using, in treatment and in recovery. The narratives were analysed using the Empirical Phenomenological Psychological five-step method (Karlsson, 1995). A total of 10 themes with 82 categories were identified. Two concepts at a higher level of abstraction above the theme-level emerged during the final stage of analysis. The concepts identified were 'emotional pain and user self-legitimization of use' and 'entrapment into habit-forming and invisible dependent use'. These concepts were reported in different ways by a majority of participants. RESULTS: Findings are presented under the following themes: (1) profile and product preferences; (2) awareness of habit forming use and harm; (3) negotiating pharmacy sales; (4) alternative sourcing routes; (5) the codeine feeling; (6) the daily routine; (7) acute and chronic side effects; (8) social isolation; (9) withdrawal and dependence and (10) help-seeking and treatment experiences. CONCLUSIONS: There is a public health and regulatory imperative to develop proactive responses tackling public availability of codeine containing medicines, risk minimisation in consumer self-treatment for pain, enhanced patient awareness of potential for habit forming use and its consequences and continued health professional pharmacovigilence.

Development of Electronic Chemotherapy Roadmaps for Pediatric Oncology Patients.

A chemotherapy roadmap is a summary of the chemotherapy plan for a pediatric oncology patient. Chemotherapy roadmaps exist as paper documents for most, if not all, pediatric oncology programs. Paper chemotherapy roadmaps are associated with risks that can negatively affect the safety of the chemotherapy process. This institution explored the feasibility of converting paper chemotherapy roadmaps into an electronic form. The pediatric information systems team developed an innovative computer application that can generate electronic chemotherapy roadmaps, and the pediatric oncology program established a novel workflow that can operationalize them. Electronic chemotherapy roadmaps have been produced for 36 treatment protocols, and 369 electronic chemotherapy roadmaps have been used for 352 pediatric oncology patients. They have functioned as designed and have not had any unintended effects. In the 5 years after their implementation, the average proportion of patient safety events involving paper or electronic chemotherapy roadmaps decreased by 78.7%. This report is the first to demonstrate the feasibility of creating and implementing electronic chemotherapy roadmaps. Continued expansion of the current library will be necessary to formally test the hypothesis that electronic chemotherapy roadmaps can decrease the risks associated with their paper counterparts and increase the safety of the chemotherapy process.

Describing and expanding the clinical phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease: case series of nine Canadian patients and literature review.

OBJECTIVE: To describe and expand the phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease (MDA5-RPILD) in Canadian patients. METHOD: All proven cases of MDA5-RPILD hospitalized in the University of Montreal's affiliated centres from 2004 to 2015 were selected for inclusion. RESULTS: Of nine consecutive patients, RPILD was the presenting manifestation in seven, whereas two patients developed RPILD 2 years after the onset of arthritis and of chronic interstitial lung disease. In the case with arthritis, RPILD was probably triggered by initiation of tumour necrosis factor-α-inhibitor therapy. In most patients (89%), RPILD was accompanied by concomitant onset of palmar/lateral finger papules, skin ulcerations, and/or mechanic's hands. All patients experienced profound weight loss over 1-2 months (mean ± SD 10.2 ± 4.8 kg). All had arthralgias and/or arthritis. Six patients were clinically amyopathic; only one patient had creatine kinase (CK) levels > 500 U/L. Initial ferritin and transaminase levels were elevated in 86% and 67% of patients, respectively. The antinuclear antibody (ANA) test was negative for nuclear and cytoplasmic staining; antisynthetase autoantibodies were negative. Three patients died; time from initial symptoms to death ranged from 7 to 15 weeks. All six survivors received mycophenolate mofetil and/or tacrolimus as part of induction and/or maintenance therapy. CONCLUSION: In an inpatient setting, RPILD associated with characteristic skin rashes, profound weight loss, articular symptoms, normal or low CK with elevated ferritin, and absent fluorescence on ANA testing should alert the clinician to the possibility of MDA5-RPILD. T-cell-mediated therapies may play a role in this highly lethal condition.

Dry Eye Disease: Concordance Between the Diagnostic Tests in African Eyes.

OBJECTIVE: To assess the concordance between the diagnostic tests for dry eye disease (DED) in a Nigerian hospital population. METHODS: The study was a hospital-based cross-sectional survey of adults (≥18 years) presenting at the eye clinic of the University of Nigeria Teaching Hospital (UNTH), Enugu; September-December, 2011. Participants' socio-demographic data were collected. Each subject was assessed for DED using the "Ocular Surface Disease Index" (OSDI) questionnaire, tear-film breakup time (TBUT), and Schirmer test. The intertest concordance was assessed using kappa statistic, correlation, and regression coefficients. RESULTS: The participants (n=402; men: 193) were aged 50.1±19.1 standard deviation years (range: 18-94 years). Dry eye disease was diagnosed in 203 by TBUT, 170 by Schirmer test, and 295 by OSDI; the concordance between the tests were OSDI versus TBUT (Kappa, κ=-0.194); OSDI versus Schirmer (κ=-0.276); and TBUT versus Schirmer (κ=0.082). Ocular Surface Disease Index was inversely correlated with Schirmer test (Spearman ρ=-0.231, P<0.001) and TBUT (ρ=-0.237, P<0.001). In the linear regression model, OSDI was poorly predicted by TBUT (ß=-0.09; 95% confidence interval (CI): -0.26 to -0.03, P=0.14) and Schirmer test (ß=-0.35, 95% CI: -0.53 to -0.18, P=0.18). CONCLUSION: At UNTH, there is poor agreement, and almost equal correlation, between the subjective and objective tests for DED. Therefore, the selection of diagnostic test for DED should be informed by cost-effectiveness and diagnostic resource availability, not diagnostic efficiency or utility.

The performance evaluation of a urine malaria test (UMT) kit for the diagnosis of malaria in individuals with fever in south-east Nigeria: cross-sectional analytical study.

BACKGROUND: Accurate rapid diagnosis is one of the important steps in the effort to reduce morbidity and mortality of malaria. Blood-specific malaria rapid diagnostic tests (RDTs) are currently in use but other body fluid specific diagnostic test kits are being developed. The aim of the present study was to evaluate the performance characteristics of a one-step Urine Malaria Test™ (UMT) dipstick in detecting Plasmodium falciparum HRP2, a poly-histidine antigen in urine of febrile patients for malaria diagnosis. METHODS: This was an observational study in which a urine-based malaria test kit was used in malaria diagnosis in a normal field setting. Two hundred and three individuals who presented with fever (≥37.5°C) at seven outpatient clinics in Enugu State during periods of high and low transmission seasons in Southeastern Nigeria were enrolled. Matched samples of urine and blood of consecutively enrolled subjects were tested with UMT and blood smear microscopy. RESULTS: With the blood smear microscopy as standard, the disease prevalence was 41.2% and sensitivity for the UMT was 83.75% (CI: 73.81 to 91.95%, Kappa 0.665, p =0.001). The UMT had an LLD of 120 parasites/µl but the sensitivity at parasite density less than ≤200 parasites/µl was 50% and 89.71% at density ≥201 parasites/µl with specificity of 83.48%. The positive and negative predictive values were 77.91% and 88.07%, respectively. CONCLUSION: The UMT showed moderate level of sensitivity compared with blood smear microscopy. The test kit requires further improvement on its sensitivity in order to be deployable for field use in malaria endemic regions.

Prevalence of presbyopia in a rural African community.

INTRODUCTION: When presbyopia (loss of accommodation of the crystalline lens with increasing age) sets in, doing near work becomes associated with headache and eye strain. Reading and writing become a challenge. Literacy levels may be low in rural communities; nevertheless some work other than reading, like sewing, sorting stone from grain and operating mobile phones, is done with dissatisfaction. This study aims to determine the prevalence of presbyopia, the unmet presbyopia need and the presbyopia correction coverage in a rural African community. METHODS: A population-based cross-sectional study was carried out in a rural population aged 35 years and greater, selected by cluster random sampling. Information was sought on biodata of the participants and they were subsequently examined. Distance visual acuity for each participant was determined. Anterior and posterior segments of the eyes were examined. Objective refraction with subjective refinement was done on all subjects with distant visual acuity less than 6/6. Near visual acuity was assessed at 40 cm with distant correction in place if required. Presbyopia was defined as inability to read N8 at 40 cm or requiring an addition of at least +1.00DS to improve near vision to at least N8. Questionnaires were administered to those identified as presbyopic on source of procurement of spectacles (if they had one) and on reasons for non-procurement of presbyopic spectacles. They were also asked to rate their difficulty with various listed near work. Data entry and analysis were done using Statistical Package for the Social Sciences v16.0 and Program for Epidemiologist v4.01 software. RESULTS: A total of 585 subjects (participation rate 81.1%) aged 35 years and greater were interviewed and examined. The prevalence of presbyopia was 63.4% (95% confidence interval (CI) 62.6-64.2%). There was increasing prevalence with increasing age. The met presbyopia need was 17.6%, unmet need was 45.8% and presbyopic correction coverage was 27.8%. The commonest reasons for not procuring presbyopic correction were 'not a priority' (21.5%) and 'cost' (21.2%). CONCLUSIONS: The prevalence of presbyopia in this rural African community is high. Many who need presbyopic correction do not have corrective spectacles.

Left heart disease: a frequent cause of early pulmonary hypertension in systemic sclerosis, unrelated to elevated NT-proBNP levels or overt cardiac fibrosis but associated with increased levels of MR-proANP and MR-proADM: retrospective analysis of a French Canadian cohort.

OBJECTIVES: Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH. METHOD: A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM). RESULTS: The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH. CONCLUSIONS: Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Dry eye disease: prevalence, distribution and determinants in a hospital-based population.

OBJECTIVES: To determine the prevalence, distribution and risk factors for dry eye disease (DED) in a tertiary ophthalmic outpatient population. METHODS: The study was a cross-sectional descriptive hospital-based survey conducted at the Eye clinic of the University of Nigeria Teaching Hospital (UNTH), Enugu, between September and December, 2011. The participants comprised adult ophthalmic outpatients aged 18 years or older. Participants' sociodemographic data were obtained. Dry eye disease was assessed subjectively with the Ocular Surface Disease Index (OSDI) questionnaire; and objectively with Schirmer's test and Tear-film Break-up Time (TBUT). An OSDI score of ≥ 50 with a TBUT of <10s or Schirmer's test reading of <10mm was considered diagnostic of DED. Descriptive and analytical statistics were performed. In all comparisons, a p<0.05 was considered statistically significant. RESULTS: The participants (n=402) comprised 193 males and 209 females who were aged 50.1 ± 19.06 SD years (range 18-94 years). The majorities of the participants were married - 74.1%, possessed formal education - 86.0% and were civil servants - 33.6%. The prevalence of DED was 19.2%. Dry eye disease was significantly associated with age>40 years (OR 1.88, 95% CI 1.06-3.35, p=0.0004), non-possession of formal education (OR 0.40, 95% CI 0.21-0.74, p=0.001) but not gender (OR 1.48, 95% CI 0.89-2.46, p=0.158). CONCLUSION: The prevalence of DED among ophthalmic outpatients at UNTH, Enugu, is comparatively high. Older age and illiteracy are predictors of DED. There is need for high index of diagnostic suspicion to prevent sight-threatening complications of DED.

A prospective pilot study investigating the musculoskeletal pain in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.

BACKGROUND: Although arthralgia is a known adverse effect of aromatase inhibitor (ai) treatment in postmenopausal breast cancer patients, few studies have carried out a comprehensive evaluation of the nature, onset, and incidence of musculoskeletal (msk) pain in these patients. We therefore used a pilot study to identify conditions or markers predictive of pain. METHODS: For 24 weeks, we monitored 30 eligible postmenopausal women starting ai therapy. Pre-existing and incident msk conditions and pain were assessed clinically and with ultrasonography of the hands and wrists. In addition, patient questionnaires were used to assess pain before and during ai therapy. Biochemical markers were measured at baseline and at regular intervals after anastrozole therapy began. Gene profiling studies were carried out before and 48 hours after the initial ai administration. RESULTS: Over the 24-week study period, 20 participants (67%) showed no pain symptoms; 5 (17%) experienced low or moderate pain at baseline, which did not increase with ai treatment; and during therapy, 5 (17%) showed exacerbation of pain attributable to osteoarthritis of the hand and to finger flexor tenosynovitis. Although all 30 participants had some degree of msk conditions before anastrozole therapy started, the pre-existing conditions did not necessarily predispose the women to increased pain during anastrozole treatment. Higher levels of urinary N-telopeptides of type i collagen were associated with the groups presenting pain, suggesting a higher extent of pre-existing bone resorption, without significant evolution over the 24-week treatment period. Slightly higher levels of 1,25(OH)(2) vitamin D(3) were observed at baseline in patients with pain increase, but did not significantly change during treatment; however, average levels of 25(OH) vitamin D(3) increased, likely because of supplementation. Although biochemical markers did not discriminate efficiently between pain groups, a signature of 166 genes in peripheral blood mononuclear cells was identified that could stratify patients into the various groups observed in this pilot study. The gene signature was enriched in components of inflammatory signalling and chemokine expression, of antitumoural immunity pathways, and of metabolic response to hormones and xenobiotics, although no clinically significant association could be made in the present study, considering the small number of patients. Nevertheless, the observed trend suggests the feasibility of developing surrogate predictive markers of msk pain. Patient compliance was high in this study and was not affected by pain exacerbation. CONCLUSIONS: Baseline msk assessment showed pre-existing causes for pain in most of the study patients before initiation of the ai. Exacerbation of existing osteoarthritis pain and tenosynovial symptoms was the primary cause of pain increase. Musculoskeletal pain assessment at baseline and prompt treatment of pain symptoms may help to optimize adherence to ai therapy. The value of routinely assessing inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate was not supported by our pilot study. Gene expression profiles in peripheral blood mononuclear cells may be further explored in larger-scale studies as stratification markers to identify patients at risk of developing arthralgia.

A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.

Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML.

To control disease before allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory AML, we used clofarabine cytoreduction. Seventeen patients received clofarabine 30-40 mg/m(2) i.v. daily for 5 days with plans to initiate conditioning during the nadir, 14 days later. Bone marrow biopsy 12 days after clofarabine showed effective cytoreduction (that is,<20% cellularity with <10% blasts) in 10 of 17 patients (59%). Ineffective cytoreduction correlated with lower PFS (3.8 vs 6.4 months; HR=2.7, 95% CI=1.10-14.29, P=0.035) and OS (5.1 vs 16.6 months; HR=2.5, 95% CI=0.98-12.17, P=0.053). Significant toxicities before HCT, attributable to clofarabine, were grade 1-2 hyperbilirubinemia (18%); grade 1-2 (59%) or grade 3-4 (18%) transaminitis; and grade 1-2 (18%) creatinine elevation. Sixteen patients proceeded to HCT infusion 22 days (median) after initiation of clofarabine. Day 100 and 2-year transplant-related mortality were 6 and 36%. Nine patients relapsed. One year PFS and OS were 25 and 38%, respectively. Two patients are alive in remission at 18 and 52 months. Clofarabine cytoreduction followed by immediate HCT is feasible with acceptable toxicity and TRM. Outcomes for this cohort of patients with refractory AML remain poor and we are studying this approach in a prospective manner.

Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. METHODS AND FINDINGS: The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). CONCLUSIONS: Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. TRIAL REGISTRATION: ClinicalTrials.Gov NCT00344006.

HIV testing and self-reported HIV status in South African men who have sex with men: results from a community-based survey.

OBJECTIVE: To investigate the characteristics of South African men who have sex with men (MSM) who (1) have been tested for HIV and (2) are HIV positive. METHODS: Data were collected from 1045 MSM in community surveys using questionnaires that were administered either face-to-face, by mail or on the internet. The mean age of the men was 29.9 years. The race distribution was 35.3% black, 17.0% coloured, 5.3% Indian and 41.1% white. RESULTS: The proportion of MSM tested for HIV was 69.7%; having been tested was independently associated with being older, being more open about one's homosexuality and being homosexually instead of bisexually attracted; black MSM, students and MSM living in KwaZulu-Natal were less likely to have been tested. Of the 728 MSM who had been tested, 14.1% (n = 103) reported to be HIV positive (9.9% of the total sample). Being HIV positive is independently associated with two factors: men who were positive were more likely to have a lower level of education and to know other people who had HIV/AIDS; race was not independently associated with HIV status among those who had been tested. CONCLUSIONS: The likelihood of having been tested for HIV seems to decrease with increasing social vulnerability. Racially, the distribution of HIV among MSM seems to differ from that of the general South African population, suggesting that while intertwined with the heterosexual epidemic there is also an epidemic among South African MSM with specific dynamics. These findings suggest that in-depth research is urgently needed to address the lack of understanding of HIV testing practices and HIV prevalence in South African MSM.

Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial.

BACKGROUND: Renal cell cancer and malignant melanoma are two types of cancer that are responsive to immunotherapy. In this phase I dose-escalation study, the feasibility of large-scale expansion and safety of administering ex vivo-expanded NK-92 cells as allogeneic cellular immunotherapy in patients with refractory renal cell cancer and melanoma were determined. METHODS: Twelve patients (aged 31-74 years) were enrolled, three per cohort at cell dose levels of 1x10(8)/m(2), 3x10(8)/m(2), 1x10(9)/m(2) and 3x10(9)/m(2). One treatment course consisted of three infusions. Eleven patients had refractory metastatic renal cell cancer; one patient had refractory metastatic melanoma. RESULTS: The NK-92 cells were expanded in X-Vivo 10 serum-free media supplemented with 500 U/mL Proleukin recombinant human interleukin-2 (rhIL-2), amino acids and 2.5% human AB plasma. Final yields of approximately 1x10(9) cells/culture bag (218-250xexpansion) over 15-17 days were achievable with >or=80% viability. Infusional toxicities of NK-92 were generally mild, with only one grade 3 fever and one grade 4 hypoglycemic episode. All toxicities were transient, resolved and did not require discontinuation of treatment. One patient was alive with disease at 4 years post-NK-92 infusion. The one metastatic melanoma patient had a minor response during the study period. One other patient exhibited a mixed response. DISCUSSION: This study establishes the feasibility of large-scale expansion and safety of administering NK-92 cells as allogeneic cellular immunotherapy in advanced cancer patients and serves as a platform for future study of this novel natural killer (NK)-cell based therapy.

Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation.

We describe treatment, outcomes and prognostic factors for patients who relapse following transplantation with a reduced intensity conditioning regimen. Seventy consecutive patients with high-risk myeloid malignancies underwent transplant and 25 (36%) relapsed, a median of 120 days later. The median percentage of bone marrow blasts at relapse was 24, the median donor chimerism was 73% and new karyotypic abnormalities occurred in 8 out of 20 (40%) evaluable patients. Twenty-one patients (84%) received aggressive treatment for relapse, including chemotherapy (60%), second hematopoietic cell transplantation (HCT; 52%) and/or donor lymphocyte infusion (DLI; 12%). Thirteen achieved a complete response (CR) and four remain in CR. Median overall survival (OS) after relapse was 6 months (95% confidence interval=2.7-9.9 months), and actuarial 1 year OS was 24%. Most deaths were due to disease progression (17/20, 85%). We did not observe an advantage for cellular therapy (DLI or second transplant) compared to chemotherapy. Salvage therapy for relapse after reduced intensity HCT is feasible, associated with low treatment-related mortality, and may result in prolonged survival in select patients. Studies exploring the optimal treatment for relapse following reduced intensity HCT are warranted.