Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b/3 trial.

BACKGROUND: Infection with the soil-transmitted helminth Strongyloides stercoralis affects up to 600 million people globally, most of whom live in rural areas with poor sanitation. If untreated, infection leads to long-lasting morbidity and might even be life-threatening. Moxidectin might be a promising alternative to ivermectin, the only currently recommended single-dose treatment. We aimed to assess whether moxidectin is non-inferior in terms of efficacy and safety compared with ivermectin. METHODS: In this randomised, double-blind, parallel-group, non-inferiority, phase 2b/3 trial in communities in Laos and Cambodia, adults aged 18-65 years were screened for the presence of S stercoralis larvae in their stool via sextuplicate quantitative Baermann assays. Using computer-generated group allocation (block randomisation stratified by infection intensity), parasitologically (two or more positive Baermann assays) and clinically eligible participants were randomly assigned (1:1) to receive single oral doses of either moxidectin (8 mg) and ivermectin-matched placebo, or ivermectin (200 µg/kg bodyweight) and moxidectin-matched placebo. The primary endpoint was cure rate assessed at 14-21 days after treatment, using the available-case population analysed according to intention-to-treat principles. Moxidectin was considered non-inferior to ivermectin if the lower limit of the two-sided 95% CI of the difference was greater than the non-inferiority margin of -10 percentage points. Safety endpoints were assessed before treatment, and at 2-3 h, 24 h, and 14-21 days after treatment. This trial is registered at ClinicalTrials.gov, NCT04056325 and NCT04848688. FINDINGS: Between Dec 6, 2020, and May 21, 2022, 4291 participants were screened, 726 of whom were enrolled and randomly assigned to moxidectin (n=363) or ivermectin (n=363). For the participants with primary outcome data, we observed a cure rate of 93·6% (95% CI 90·5 to 96·0; 324 of 346 participants) in the moxidectin group and 95·7% (93·0 to 97·6; 335 of 350 participants) in the ivermectin group, resulting in a between-group difference of -2·1 percentage points (95% CI -5·5 to 1·3). The most common adverse events were abdominal pain (32 [9%] of 363 with moxidectin vs 34 [9%] of 363 with ivermectin) and headache (25 [7%] vs 30 [8%]), which were predominantly mild and transient. INTERPRETATION: Moxidectin was non-inferior to ivermectin in terms of efficacy in the treatment of strongyloidiasis. Additionally, both drugs had a similar safety profile. The fixed dose and lower cost of moxidectin compared with ivermectin make it a valuable alternative for people with strongyloidiasis. FUNDING: Swiss National Science Foundation.

Ivermectin and moxidectin against soil-transmitted helminth infections.

Ivermectin and moxidectin, two macrocyclic lactones, are potent antiparasitic drugs currently registered and mainly used against filarial diseases; however, their potential value for improved soil-transmitted helminth (STH) control has been acknowledged. This review provides insights on recent studies evaluating the efficacy of ivermectin and moxidectin as single or coadministered therapy against human soil-transmitted helminthiases (including Strongyloides stercoralis infections) and on pharmacokinetic/pharmacodynamic parameters measured in treated populations. Furthermore, we discuss current gaps for research, highlight advantages - but also existing challenges - for uptake of ivermectin and/or moxidectin treatment schemes into routine STH control in endemic countries.

Engineered Nonviral Protein Cages Modified for MR Imaging.

Diagnostic medical imaging utilizes magnetic resonance (MR) to provide anatomical, functional, and molecular information in a single scan. Nanoparticles are often labeled with Gd(III) complexes to amplify the MR signal of contrast agents (CAs) with large payloads and high proton relaxation efficiencies (relaxivity, r1). This study examined the MR performance of two structurally unique cages, AaLS-13 and OP, labeled with Gd(III). The cages have characteristics relevant for the development of theranostic platforms, including (i) well-defined structure, symmetry, and size; (ii) the amenability to extensive engineering; (iii) the adjustable loading of therapeutically relevant cargo molecules; (iv) high physical stability; and (v) facile manufacturing by microbial fermentation. The resulting conjugates showed significantly enhanced proton relaxivity (r1 = 11-18 mM-1 s-1 at 1.4 T) compared to the Gd(III) complex alone (r1 = 4 mM-1 s-1). Serum phantom images revealed 107% and 57% contrast enhancements for Gd(III)-labeled AaLS-13 and OP cages, respectively. Moreover, proton nuclear magnetic relaxation dispersion (1H NMRD) profiles showed maximum relaxivity values of 50 mM-1 s-1. Best-fit analyses of the 1H NMRD profiles attributed the high relaxivity of the Gd(III)-labeled cages to the slow molecular tumbling of the conjugates and restricted local motion of the conjugated Gd(III) complex.

Virus variant-specific clinical performance of SARS coronavirus two rapid antigen tests in point-of-care use, from November 2020 to January 2022.

OBJECTIVES: Antigen rapid diagnostic tests (RDTs) for SARS coronavirus 2 (SARS-CoV-2) are quick, widely available, and inexpensive. Consequently, RDTs have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable clinical and large-scale performance data specific to a SARS-CoV-2 virus variant of concern (VOC) are limited, especially for the Omicron VOC. The aim of this study was to compare RDT performance among different VOCs. METHODS: This single-centre prospective performance assessment compared RDTs from three manufacturers (NADAL, Panbio, MEDsan) with RT-qPCR including deduced standardized viral load from oropharyngeal swabs for detection of SARS-CoV-2 in a clinical point-of-care setting from November 2020 to January 2022. RESULTS: Among 35 479 RDT/RT-qPCR tandems taken from 26 940 individuals, 164 of the 426 SARS-CoV-2 positive samples tested true positive with an RDT corresponding to an RDT sensitivity of 38.50% (95% CI, 34.00-43.20%), with an overall specificity of 99.67% (95% CI, 99.60-99.72%). RDT sensitivity depended on viral load, with decreasing sensitivity accompanied by descending viral load. VOC-dependent sensitivity assessment showed a sensitivity of 42.86% (95% CI, 32.82-53.52%) for the wild-type SARS-CoV-2, 43.42% (95% CI, 32.86-54.61%) for the Alpha VOC, 37.67% (95% CI, 30.22-45.75%) for the Delta VOC, and 33.67% (95% CI, 25.09-43.49%) for the Omicron VOC. Sensitivity in samples with high viral loads of ≥106 SARS-CoV-2 RNA copies per mL was significantly lower in the Omicron VOC (50.00%; 95% CI, 36.12-63.88%) than in the wild-type SARS-CoV-2 (79.31%; 95% CI, 61.61-90.15%; p 0.015). DISCUSSION: RDT sensitivity for detection of the Omicron VOC is reduced in individuals infected with a high viral load, which curtails the effectiveness of RDTs. This aspect furthert: limits the use of RDTs, although RDTs are still an irreplaceable diagnostic tool for rapid, economic point-of-care and extensive SARS-CoV-2 screening.

Pharmacokinetics of Ascending Doses of Praziquantel in Adults Infected with Opisthorchis felineus in Western Siberia, Russian Federation.

Opisthorchiasis due to the liver fluke Opisthorchis felineus is highly prevalent in rural regions of Western Siberia, causing severe liver and bile duct maladies. Praziquantel administered as a three-dose regimen is the only drug used to treat O. felineus-infected individuals. A simpler single-dose treatment might serve as an alternative. The aim of this study was to compare the pharmacokinetic (PK) properties of single, ascending doses of praziquantel compared to multiple dosing in patients infected with O. felineus to contribute to updated treatment guidelines. Dried blood spots (DBSs) of 110 adults were collected at 11 time points post-drug administration at single oral doses of 20, 40, and 60 mg/kg, as well as 3× 20 mg/kg (4 h dosing interval). DBS samples were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and PK parameters were obtained for R-, S-, and R-trans-4-OH-praziquantel employing noncompartmental analysis. We observed the highest drug exposure for all analytes when the triple-dose scheme was used; area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 8.04, 27.75, and 36.38 µg/mL·h were obtained, respectively. Maximal plasma concentrations (Cmax) values of 1.72, 4.89, and 2.69 µg/mL were calculated for R-, S-, and R-trans-4-OH-praziquantel, respectively, when patients were given a single 60-mg/kg dose, and they peaked at 1.5 and 2 h for the enantiomers and at 3 h for the metabolite. The herein-generated PK data, together with results that will be obtained from the integrated efficacy study, lay the groundwork for a possibly optimized treatment scheme for O. felineus-infected patients.

Pharmacokinetic modelling and simulation to optimize albendazole dosing in hookworm- or Trichuris trichiura-infected infants to adults.

BACKGROUND: Albendazole is the most commonly used drug in preventive chemotherapy programmes against soil-transmitted helminth (STH) infections, with the standard dose of 400 mg resulting in suboptimal clinical outcomes. Population pharmacokinetic (PK) models that could inform dosing strategies are not yet available. METHODS: A population pharmacokinetic model was developed based on micro-blood samples collected from 252 patients aged 2 to 65 years, infected with either hookworm or Trichuris trichiura and treated with albendazole doses ranging from of 200 to 800 mg. An exposure-response analysis was performed relating albendazole and its two metabolites to cure rates and egg reduction rates (ERR). Finally, model-based simulations were conducted to determine equivalent exposure coverage in infants to adults. RESULTS: A population PK model, with one distribution compartment for each compound and one peripheral compartment, following oral administration with a lag time, assuming first-order absorption and linear elimination, best described the concentration-time profiles. Clearance and volume parameters were scaled to body size (weight for albendazole and height for albendazole sulfoxide and sulfone). Dose proportionality was observed for the active metabolite, albendazole sulfoxide, but only in hookworm-infected individuals, with increasing exposure resulting in increased ERR. Exposure of sulfoxide was lowest in the tallest individuals. CONCLUSIONS: Pharmacometric simulations indicate that doses up to 800 mg could further increase albendazole efficacy in hookworm-infected adults, whereas the standard dose of 400 mg is sufficient in the youngest age cohorts. In the absence of evidence-based arguments for adjusting albendazole doses in T. trichiura-infected individuals, the search for new treatment options is further emphasized.

Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed-Dose Treatment Regimen.

BACKGROUND: Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies. METHODS: A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy). RESULTS: A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively. CONCLUSION: We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT04056325).

Optimizing moxidectin dosing for Strongyloides stercoralis infections: Insights from pharmacometric modeling.

Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability profile. Yet, owing to the unique life cycle of Strongyloides stercoralis (S. stercoralis) that entails internal autoinfection, a curative treatment would be desirable. Population-based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure-efficacy response relationship of moxidectin in treating S. stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post-treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve-receiver operating characteristic [AUC-ROC] 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC0-24 or maximum concentration [Cmax ]) to baseline infection intensity. Pharmacometric simulations indicate that with a minimum dose of 4 mg a maximum cure rate of ~ 95% is established in the low infection intensity group (larvae per gram [LPG] ≥0.4-1), whereas in the moderate-to-high intensity group (LPG >1) the cure rate plateaus at ~ 87%, following an 8 mg dose. To enhance efficacy further, studies using repeated dosing based on the duration of the autoinfection cycle, for example a two-dose regimen 3 weeks apart should be considered. Simulations revealed similar Cmax in both treatment courses of a two-dose regimen; hence safety should not be a concern. Collectively, our results provide evidence-based guidance for enhanced dosing strategies and should be considered when designing future treatment strategies.

Efficacy and safety of moxidectin and albendazole compared to ivermectin and albendazole co-administration in adolescents infected with Trichuris trichiura: a randomized controlled trial protocol.

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The trial will be open-label with blinded outcome assessors. The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations' superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment and pharmacokinetic/  pharmacodynamic parameters will also be assessed. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021).

Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial.

BACKGROUND: Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of moxidectin in Strongyloides stercoralis-infected patients. METHODS: We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18-65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of moxidectin, 4 mg of moxidectin, 6 mg of moxidectin, 8 mg of moxidectin, 10 mg of moxidectin, 12 mg of moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato-Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic Emax models. Safety was evaluated in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04056325, and is complete. FINDINGS: Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of moxidectin had a predicted cure rate of 75% (95% CI 59-87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5-31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76-88; 26 [90%] of 29 cured) at 4 mg to 86% (79-90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80-92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80-93; 29 [97%] of 30 cured) at 10 mg and 88% (80-93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild. INTERPRETATION: 4-12 mg of moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy. FUNDING: Fondazione Adiuvare.

Development and validation of an LC-MS/MS method for the quantification of the anthelmintic drug moxidectin in a volumetric absorptive microsample, blood, and plasma: Application to a pharmacokinetic study of adults infected with Strongyloides stercoralis in Laos.

Moxidectin is a promising candidate for addition to the lean repertoire of drugs against neglected tropical diseases (NTD) including strongyloidiasis. Pharmacokinetic (PK) and -dynamic studies are required to support its clinical development. Microsampling approaches enable PK studies in the challenging environments where NTDs are most prevalent, due to simplified collection and processing. We developed a liquid chromatography tandem mass spectrometry method for the sensitive quantification of moxidectin in human blood obtained by capillary sampling with the microsampling device Mitra® compared to blood and plasma obtained by venous sampling. Sample preparation consisted of protein precipitation, evaporation and reconstitution and also included phospholipid filtration for blood and plasma. Moxidectin was detected by multiple reaction monitoring (640.4 â†’ 528.5 m/z) using a Luna C8(2) (30 × 2.0 mm, 3 µm particle size, 100 Å) analytical column with a gradient program of 6 min duration. Validation was performed with respect to accuracy, precision, sensitivity, selectivity, linearity, stability, recovery, and haematocrit influence with a limit of quantification of 0.5 and 2.5 ng/mL, for venous and capillary blood respectively. Moxidectin was stable up to 2 months at storage condition (blood and plasma: -20 °C, microsamples: room temperature), 3 cycles of temperature shift, for at least 4 h on the bench-top and 24 h in the autosampler (4 °C). Deviations of inter- and intra-assay accuracy and precision were smaller than 12.6% and recoveries were in the range of 80.7-111.2%. The method was applied to samples obtained from nine Strongyloides stercoralis-infected adults from northern Laos. A good agreement in the time-concentration profiles of moxidectin and a high consistency in PK parameters was found between the different matrixes and sampling strategies: e.g. identical time to reach maximal concentration of 4.0 h and a similar maximal concentration of 83.9-88.5 ng/mL of moxidectin. The simple and practical capillary procedure using Mitra® microsampling has been demonstrated to be suitable for PK studies of moxidectin and will pave the way for future PK studies.

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model.

Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30-100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of moxidectin on Strongyloides ratti larvae (L3) and adult females and the activity as well as the pharmacokinetics of moxidectin in S. ratti infected rats. In vitro, moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L3 and adults in the range of 0.08-1.44 µM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 µg/kg of moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 µg/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng × h/mL. The half-life in rats was 9 h, and moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of moxidectin in the treatment of S. ratti as a model of Strongyloides spp. and, as such, supports moving moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.

Efficacy and Safety of Albendazole in Hookworm-infected Preschool-aged Children, School-aged Children, and Adults in Côte d'Ivoire: A Phase 2 Randomized, Controlled Dose-finding Trial.

BACKGROUND: Infections with hookworms affect about half a billion people worldwide. Recommended therapy includes 400 mg of albendazole, which is moderately efficacious. Higher doses have been rarely assessed. METHODS: A randomized, controlled dose-finding trial was conducted in Côte d'Ivoire with the aim of recruiting 120 preschool-aged children (PSAC), 200 school-aged children (SAC), and 200 adults. Eligible PSAC were randomized 1:1:1 to 200 mg, 400 mg, or 600 mg of albendazole; the other age groups were randomized 1:1:1:1:1 to placebo or 200 mg, 400 mg, 600 mg, or 800 mg. The primary outcome was cure rates (CRs) assessed 14-21 days post-treatment by quadruplicate Kato-Katz thick smears. Hyperbolic Emax models were used to determine dose-response. RESULTS: 38 PSAC, 133 SAC, and 196 adults were enrolled. In adults, predicted CRs increased with ascending doses of albendazole, with a CR of 74.9% (95% confidence interval [CI], 55.6%-87.7%) in the 800-mg arm. Observed CRs increased with ascending doses of albendazole reaching a maximum of 94.1% (95% CI, 80.3%-99.3%). In SAC, the predicted dose-response curve increased marginally, with CRs ranging from 64.0% in the 200-mg arm to 76.0% in the 800-mg arm. Sample size in PSAC was considered too small to derive meaningful conclusions. 10.7% and 5.1% of participants reported any adverse event at 3 hours and 24 hours post-treatment, respectively. CONCLUSIONS: A single 800-mg albendazole dose provides higher efficacy against hookworm and is well tolerated in adults and should be considered for community-based strategies targeting adults. For PSAC and SAC, current recommendations suffice. CLINICAL TRIALS REGISTRATION: NCT03527745.

Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements.

The homotrimeric ligand tumor necrosis factor α (TNFα) is a key cytokine and immune regulator; however, when deregulated, it leads to several major chronic inflammatory diseases. Perturbation of the protein-protein interface has proven to be an efficient strategy to inactivate TNFα, but the atomic-resolution mechanism of its inactivation remains poorly understood. Here, we probe the solution structure and dynamics of active and inactive TNFα using NMR spectroscopy. The data reveal that TNFα undergoes motions on different time scales. Furthermore, by site-directed mutagenesis of residues at the trimerization interface and by targeting the interface with a low molecular weight inhibitor, we show that TNFα retains its overall structure and trimeric state. However, upon perturbation, TNFα exhibits increased conformational dynamics spanning from the trimerization interface to the regions mediating receptor binding. These findings provide novel insights into the inactivation mechanism of TNFα and the basis for strategies to target TNFα activity.

Between the Vinca and Linearbandkeramik Worlds: The Diversity of Practices and Identities in the 54th-53rd Centuries cal BC in Southwest Hungary and Beyond.

Perhaps nowhere in European prehistory does the idea of clearly-defined cultural boundaries remain more current than in the initial Neolithic, where the southeast-northwest trend of the spread of farming crosses what is perceived as a sharp divide between the Balkans and central Europe. This corresponds to a distinction between the Vinca culture package, named for a classic site in Serbia, with its characteristic pottery assemblage and absence of longhouses, and the Linearbandkeramik (LBK), with equally diagnostic but different pottery, and its apparently culturally-diagnostic longhouses, extending in a more northerly belt through central Europe westward to the Dutch coast. In this paper we question the concept of such a clear division through a presentation of new data from the site of Szederkény-Kukorica-dulo. A large settlement in southeast Transdanubia, Hungary, excavated in advance of road construction, Szederkény is notable for its combination of pottery styles, variously including Vinca A, Raziste and LBK, and longhouses of a kind otherwise familiar from the LBK world. Formal modelling of its date establishes that the site probably began in the later 54th century cal BC, lasting until the first decades of the 52nd century cal BC. Occupation, featuring longhouses, pits and graves, probably began at the same time in the eastern and western parts of the settlement, starting a decade or two later in the central part; the western part was probably the last to be abandoned. Vinca pottery is predominantly associated with the eastern and central parts of the site, and Raziste pottery with the west. Formal modelling of the early history of longhouses in the LBK world suggests their emergence in the Formative LBK of Transdanubia c. 5500 cal BC followed by rapid dispersal in the middle of the 54th century cal BC, associated with the 'earliest' (älteste) LBK. The adoption of longhouses at Szederkény thus appears to come a few generations after the start of this 'diaspora'. Rather than explaining the mixture of things, practices and perhaps people at Szederkény with reference to problematic notions such as hybridity, we propose instead a more fluid and varied vocabulary, encompassing combination and amalgamation, relationships and performance in the flow of social life, and networks; this makes greater allowance for diversity and interleaving in a context of rapid change.

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND: HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. METHODS: Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/µl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/µl. RESULTS: No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/µl compared to -37.42 ± 10.77 cells/µl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. CONCLUSIONS: This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT01299948.

Widespread exploitation of the honeybee by early Neolithic farmers.

The pressures on honeybee (Apis mellifera) populations, resulting from threats by modern pesticides, parasites, predators and diseases, have raised awareness of the economic importance and critical role this insect plays in agricultural societies across the globe. However, the association of humans with A. mellifera predates post-industrial-revolution agriculture, as evidenced by the widespread presence of ancient Egyptian bee iconography dating to the Old Kingdom (approximately 2400 BC). There are also indications of Stone Age people harvesting bee products; for example, honey hunting is interpreted from rock art in a prehistoric Holocene context and a beeswax find in a pre-agriculturalist site. However, when and where the regular association of A. mellifera with agriculturalists emerged is unknown. One of the major products of A. mellifera is beeswax, which is composed of a complex suite of lipids including n-alkanes, n-alkanoic acids and fatty acyl wax esters. The composition is highly constant as it is determined genetically through the insect's biochemistry. Thus, the chemical 'fingerprint' of beeswax provides a reliable basis for detecting this commodity in organic residues preserved at archaeological sites, which we now use to trace the exploitation by humans of A. mellifera temporally and spatially. Here we present secure identifications of beeswax in lipid residues preserved in pottery vessels of Neolithic Old World farmers. The geographical range of bee product exploitation is traced in Neolithic Europe, the Near East and North Africa, providing the palaeoecological range of honeybees during prehistory. Temporally, we demonstrate that bee products were exploited continuously, and probably extensively in some regions, at least from the seventh millennium cal BC, likely fulfilling a variety of technological and cultural functions. The close association of A. mellifera with Neolithic farming communities dates to the early onset of agriculture and may provide evidence for the beginnings of a domestication process.

Eight-channel transceiver RF coil array tailored for ¹H/¹9F MR of the human knee and fluorinated drugs at 7.0 T.

The purpose of this study was to evaluate the feasibility of an eight-channel dual-tuned transceiver surface RF coil array for combined (1)H/(19)F MR of the human knee at 7.0 T following application of (19)F-containing drugs. The (1)H/(19)F RF coil array includes a posterior module with two (1)H loop elements and two anterior modules, each consisting of one (1)H and two (19)F elements. The decoupling of neighbor elements is achieved by a shared capacitor. Electromagnetic field simulations were performed to afford uniform transmission fields and to be in accordance with RF safety guidelines. Localized (19)F MRS was conducted with 47 and 101 mmol/L of flufenamic acid (FA) ­ a (19)F-containing non-steroidal anti-inflammatory drug ­ to determine T1 and T2 and to study the (19)F signal-to-dose relationship. The suitability of the proposed approach for (1)H/(19)F MR was examined in healthy subjects. Reflection coefficients of each channel were less than -17 dB and coupling between channels was less than -11 dB. Q(L)/Q(U) was less than 0.5 for all elements. MRS results demonstrated signal stability with 1% variation. T1 and T2 relaxation times changed with concentration of FA: T1 /T2 = 673/31 ms at 101 mmol/L and T1 /T2 = 616/26 ms at 47 mmol/L. A uniform signal and contrast across the patella could be observed in proton imaging. The sensitivity of the RF coil enabled localization of FA ointment administrated to the knee with an in-plane spatial resolution of (1.5 × 1.5) mm(2) achieved in a total scan time of approximately three minutes, which is well suited for translational human studies. This study shows the feasibility of combined (1)H/(19)F MRI of the knee at 7.0 T and proposes T1 and T2 mapping methods for quantifying fluorinated drugs in vivo. Further technological developments are necessary to promote real-time bioavailability studies and quantification of (19)F-containing medicinal compounds in vivo.