Metal Complexes of Phosphinic Acids: Part XIII*-Dithiophosphinic Acid Complexes of UO2(VI) & In(III)

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The impact of an intervention to introduce malaria rapid diagnostic tests on fever case management in a high transmission setting in Uganda: A mixed-methods cluster-randomized trial (PRIME).

Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 95\% CI: 0.56, 1.17 p = 0.24). Most children (76.0\%) tested positive by reference mRDT, but many were not prescribed AL (22.5\% intervention versus 25.9\% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3\% invention vs 42.4\% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust

Toward the Discovery of Vaccine Adjuvants: Coupling In Silico Screening and In Vitro Analysis of Antagonist Binding to Human and Mouse CCR4 Receptors

BACKGROUND: Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ regulatory T cells (Tregs) to down-regulate immune responses. METHODOLOGY: Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs. SIGNIFICANCE: Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice

Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency.

Fetal growth restriction (FGR) is the most common pregnancy complication in developed countries. Pregnancies affected by FGR, frequently concur with complications and high risk of neonatal morbidity and mortality. To date, no approved treatment is available for pregnant women affected with FGR. The objective of this study was to investigate the contribution of galectin-3 (gal-3), a β-galactoside binding protein involved in pregnancy, placental function and fetal growth. We demonstrated that lack of gal-3 during mouse pregnancy leads to placental dysfunction and drives FGR in the absence of a maternal preeclampsia syndrome. Analysis of gal-3 deficient dams revealed placental inflammation and malperfusion, as well as uterine natural killer cell infiltration with aberrant activation. Our results also show that FGR is associated with a failure to increase maternal circulating gal-3 levels during the second and third trimester in human pregnancies. Placentas from human pregnancies affected by FGR displayed lower gal-3 expression, which correlated with placental dysfunction. These data highlight the importance of gal-3 in the promotion of proper placental function, as its absence leads to placental disease and subsequent FGR

Safety and Allele-Specific Immunogenicity of a Malaria Vaccine in Malian Adults: Results of a Phase I Randomized Trial

OBJECTIVES: The objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels. DESIGN: We conducted a randomized, double-blind, controlled phase I clinical trial. SETTING: Bandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria. PARTICIPANTS: Forty healthy, malaria-experienced Malian adults aged 18–55 y were enrolled. INTERVENTIONS: The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-1(42)) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y. OUTCOME MEASURES: Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-1(42) and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured. RESULTS: Transient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-1(42) antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-1(42) alleles and their subunits. CONCLUSIONS: FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-1(42) antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine

Boomerang: Rebounding the consequences of reputation feedback on crowdsourcing platforms

Paid crowdsourcing platforms suffer from low-quality workand unfair rejections, but paradoxically, most workers and requesters have high reputation scores. These inflated scores, which make high-quality work and workers difficult to find,stem from social pressure to avoid giving negative feedback. We introduce Boomerang, a reputation system for crowdsourcing that elicits more accurate feedback by rebounding the consequences of feedback directly back onto the person who gave it. With Boomerang, requesters find that their highly rated workers gain earliest access to their future tasks, and workers find tasks from their highly-rated requesters at the top of their task feed. Field experiments verify that Boomerang causes both workers and requesters to provide feedback that is more closely aligned with their private opinions. Inspired by a game-theoretic notion of incentive-compatibility, Boomerang opens opportunities for interaction design to incentivize honest reporting over strategic dishonesty

Visceral Leishmaniasis in Muzaffarpur District, Bihar, India from 1990 to 2008

BACKGROUND: Visceral Leishmaniasis (VL) is a vector-borne disease transmitted by Phlebotomus argentipes. To understand the VL seasonality, annual and monthly variations of VL incidence and its relationship to meteorological variables, the numbers of VL cases reported in Muzaffarpur district, Bihar, India from 1990 to 2008 were studied. METHODS: Annual VL incidence per 10,000 and the total number of annual VL cases reported at block Community Health Centres (CHC), Public Hospitals or Non-Governmental Organisations (NGO) and the number of VL cases per month from 2000 to 2008 as well as the monthly average of cases for 2000-08, 2000-04 and 2005-08 periods along with the monthly averages of temperature, rainfall and relative humidity were plotted. VL Standardised Incidence Ratios per block were computed for the periods of 1990-1993, 1994-1998, 1999-2004 and 2005-2008 and month wise from 2002 to 2008. A negative binomial regression model was used to evaluate the association between meteorological variables and the number of VL cases per month from 2000 to 2008. RESULTS: A total of 68,358 VL cases were reported in Muzaffarpur district from 1990 to 2008, ranging from 1,2481 in 1992 to 1,161 in 2001. The blocks with the highest number of cases shifted from East (1990-98) to West (1999-2008). Monthly averages of cases ranged from 149 to 309, highest peak in March-April and another one in July. Monthly VL incidence was associated positively to rainfall and negatively to relative humidity and the numbers of VL cases in the previous month. INTERPRETATION: The number of cases reported to the public health sector allowed the describing of the spatial distribution and temporal variations in the Muzaffarpur from 1990 to 2008. However, to assess the actual VL burden, as well as the efficacy of the control measures applied in the district, reporting from private practices and NGOs should be encouraged

Severe fetal growth restriction at 26-32 weeks: key messages from the TRUFFLE study.

The Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE) was a prospective, multicenter, unblinded, randomized trial that ran between 1 January 2005 and 1 October 2010 in 20 European centers1. It studied singleton pregnancies at 26–32weeks of gestation with a diagnosis of fetal growth restriction (FGR), defined as abdominal circumference95th percentile). In order to assess whether changes in the fetal ductus venosus (DV) Doppler waveform or short-term variation (STV) on cardiotocography (CTG) should be used as a trigger for delivery in these pregnancies, the 503 included women were randomly allocated to one of three ‘timing-of-delivery’ plans (with 1 : 1 : 1 randomization).</p

Establishment of an In Vitro Assay for Assessing the Effects of Drugs on the Liver Stages of Plasmodium vivax Malaria

Plasmodium vivax (Pv) is the second most important human malaria parasite. Recent data indicate that the impact of Pv malaria on the health and economies of the developing world has been dramatically underestimated. Pv has a unique feature in its life cycle. Uninucleate sporozoites (spz), after invasion of human hepatocytes, either proceed to develop into tens of thousands of merozoites within the infected hepatocytes or remain as dormant forms called hypnozoites, which cause relapses of malaria months to several years after the primary infection. Elimination of malaria caused by Pv will be facilitated by developing a safe, highly effective drug that eliminates Pv liver stages, including hypnozoites. Identification and development of such a drug would be facilitated by the development of a medium to high throughput assay for screening drugs against Pv liver stages. We undertook the present pilot study to (1) assess the feasibility of producing large quantities of purified, vialed, cryopreserved Pv sporozoites and (2) establish a system for culturing the liver stages of Pv in order to assess the effects of drugs on the liver stages of Pv. We used primaquine (PQ) to establish this assay model, because PQ is the only licensed drug known to clear all Pv hepatocyte stages, including hypnozoites, and the effect of PQ on Pv hepatocyte stage development in vitro has not previously been reported. We report that we have established the capacity to reproducibly infect hepatoma cells with purified, cyropreserved Pv spz from the same lot, quantitate the primary outcome variable of infected hepatoma cells and demonstrate the inhibitory activity of primaquine on the infected hepatoma cells. We have also identified small parasite forms that may be hypnozoites. These data provide the foundation for finalizing a medium throughput, high content assay to identify new drugs for the elimination of all Pv liver stages