Intraspecific niche models for the invasive ambrosia beetle Xylosandrus crassiusculus suggest contrasted responses to climate change.

Xylosandrus crassiusculus is an invasive ambrosia beetle comprising two differentiated genetic lineages, named cluster 1 and cluster 2. These lineages invaded different parts of the world at different periods of time. We tested whether they exhibited different climatic niches using Schoener's D and Hellinger's I indices and modeled their current potential geographical ranges using the Maxent algorithm. The resulting models were projected according to future and recent past climate datasets for Europe and the Mediterranean region. The future projections were performed for the periods 2041-2070 and 2071-2100 using 3 SSPs and 5 GCMs. The genetic lineages exhibited different climate niches. Parts of Europe, the Americas, Sub-Saharan Africa, Asia, and Oceania were evaluated as suitable for cluster 1. Parts of Europe, South America, Central and South Africa, Asia, and Oceania were considered as suitable for cluster 2. Models projection under future climate scenarios indicated a decrease in climate suitability in Southern Europe and an increase in North Eastern Europe in 2071-2100. Most of Southern and Western Europe was evaluated as already suitable for both clusters in the early twentieth century. Our results show that large climatically suitable regions still remain uncolonized and that climate change will affect the geographical distribution of climatically suitable areas. Climate conditions in Europe were favorable in the twentieth century, suggesting that the recent colonization of Europe is rather due to an increase in propagule pressure via international trade than to recent environmental changes.

Effects of the foot strike pattern on muscle activity and neuromuscular fatigue in downhill trail running.

Minimizing musculo-skeletal damage and fatigue is considered paramount for performance in trail running. Our purposes were to investigate the effects of the foot strike pattern and its variability on (a) muscle activity during a downhill trail run and (b) immediate and delayed neuromuscular fatigue. Twenty-three runners performed a 6.5-km run (1264 m of negative elevation change). Electromyographic activity of lower-limb muscles was recorded continuously. Heel and metatarsal accelerations were recorded to identify the running technique. Peripheral and central fatigue was assessed in knee extensors (KE) and plantar flexors (PF) at Pre-, Post-, and 2 days post downhill run (Post2d). Anterior patterns were associated with (a) higher gastrocnemius lateralis activity and lower tibialis anterior and vastus lateralis activity during the run and (b) larger decreases in KE high-frequency stimulus-evoked torque Post and larger decrements in KE MVC Post2d. High patterns variability during the run was associated with (a) smaller decreases in KE Db100 Post and MVC Post2d and (b) smaller decreases in PF MVC Post and Post2d. Anterior patterns increase the severity of KE peripheral fatigue. However, high foot strike pattern variability during the run reduced acute and delayed neuromuscular fatigue in KE and PF.

Acute and delayed peripheral and central neuromuscular alterations induced by a short and intense downhill trail run.

Downhill sections are highly strenuous likely contributing to the development of neuromuscular fatigue in trail running. Our purpose was to investigate the consequences of an intense downhill trail run (DTR) on peripheral and central neuromuscular fatigue at knee extensors (KE) and plantar flexors (PF). Twenty-three runners performed a 6.5-km DTR (1264-m altitude drop) as fast as possible. The electromyographic activity of vastus lateralis (VL) and gastrocnemius lateralis (GL) was continuously recorded. Neuromuscular functions were assessed Pre-, Post-, and 2-day Post-DTR (Post2d). Maximal voluntary torques decreased Post (∼ -19% for KE, ∼ -25% for PF) and Post2d (∼ -9% for KE, ∼ -10% for PF). Both central and peripheral dysfunctions were observed. Decreased KE and PF voluntary activation (VA), evoked forces, VL M-wave amplitude, and KE low-frequency fatigue were observed at Post. Changes in VL M-wave amplitude were negatively correlated to VL activity during DTR. Changes in PF twitch force and VA were negatively correlated to GL activity during DTR. The acute KE VA deficit was about a third of that reported after ultramarathons, although peripheral alterations were similar. The prolonged force loss seems to be mainly associated to VA deficit likely induced by the delayed inflammatory response to DTR-induced ultrastructural muscle damage.

Shiga toxigenic and enteropathogenic Escherichia coli in water and fish from pay-to-fish ponds.

UNLABELLED: Escherichia coli is part of the normal microflora of the intestines of mammals. However, among the enteric pathogens, it is one of the leading causes of intestinal diseases, especially Shiga toxigenic E. coli, which can cause diarrhoea, haemorrhagic colitis and complications like haemolytic uraemic syndrome and thrombotic thrombocytopaenic purpura. Escherichia coli is considered a serious public health problem. Water and fish samples were subjected to biochemical tests to confirm the presence of E. coli and by PCR to verify the presence of pathogenic strains (O157, enteropathogenic and shiga toxigenic) in water and fish (skin, gastrointestinal tract and muscles) from pay-to-fish ponds located in the Córrego Rico watershed in the northeastern region of the state of São Paulo, Brazil. Of the 115 E. coli isolates from fish or water, five (4·34%) contained eae and stx2 genes, one had only the eae gene and two had the stx1 gene. An isolate containing the stx2 gene was also found in the water sample. In addition, eight isolates (6·95%) from the fish gastrointestinal tract contained rfbEO157:H7 (O157 gene), and three (2·61%) contained stx2 and eae genes, demonstrating the potential risk to the environment and public health. The results provide useful basic information for the proper management of these environments and animals in order to prevent faecal pollution, reducing health risks to the Brazilian population. SIGNIFICANCE AND IMPACT OF THE STUDY: Pay-to-fish ponds are a common commercial activity in Brazil. Samples of water and Oreochromis niloticus were examined by PCR to detect the presence of pathogenic strains of Escherichia coli (O157, enteropathogenic and shiga toxigenic). Several pathogenic strains were detected in this study, providing useful epidemiological information for the proper management of these environments and animals in order to prevent faecal pollution, reducing health risks to the Brazilian population.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

Influence of Ergometer Design on Physiological Responses during Rowing.

The aim of this study was to compare the physiological responses and rowing efficiency on 2 different rowing ergometers: stationary vs. dynamic ergometers manufactured by Concept2. 11 oarswomen and oarsmen rowed 4 min at 60% and 70% of peak power output on both ergometers (randomized order). Power output, stroke rate, heart rate, oxygen uptake, carbon dioxide production, lactate accumulation and rating of perceived exertion were recorded at each stage on the 2 ergometers. Gross and net efficiencies were computed. Exercise intensity was associated with increases in all parameters. Rowing on dynamic ergometer was associated with higher heart rate, oxygen uptake, carbon dioxide production and stroke rate, concomitantly to lower blood lactate accumulation but also to lower gross and net efficiencies. The present study showed that rowing efficiency and blood lactate accumulation were lower on the Concept2 dynamic ergometer than on its stationary counterpart. If the use of the Concept2 dynamic ergometer may provide some advantages (reduced risk of injuries), its utilization requires a specific evaluation of physiological responses during an incremental exercise for an adapted management of training.

Potential effects of racket grip size on lateral epicondilalgy risks.

The effects of tennis racket grip size on the forces exerted by muscles affecting lateral epicondylalgia (LE) were assessed in this study. Grip forces and joint moments applied on the wrist were quantified under three different handle size conditions, with and without induced muscle fatigue for intermediate and advanced players. The obtained experimental results were then used as input data of a biomechanical model of the hand. This simulation aimed to quantify the impact of grip strength modulation obtained in the experiment on the wrist extensor muscle forces. Our results show that there is an optimal grip diameter size defined as the handle inducing a reduced grip force during the stroke, in both fatigued and non-fatigued sessions. The results of the simulation suggested that extensor muscles were highly employed during forehand strokes, which confirms that the mechanical overuse of extensor tendons is a potential risk factor for tennis elbow occurrence. The handle grip size appeared to be a significant factor to reduce this extensor tendon loading. This suggests that grip size should be taken into account by players and designers in order to reduce the mechanical risk factors of overuse injury occurrence.

Comparative analysis of the dispersion modeling and dose projection results performed under BARCO international project.

Radiological assessments on zones to take protective actions in case of a nuclear or radiological emergency involve a series of real-time forecasts of radiological impact on the public at various distances from the release point, using actual weather or forecast data, information on the source term or facility status, and primary radiation monitoring data. This practice is implemented during the operation of emergency centers around the world in order to promptly report the occurrence and possible consequences of radiological accidents in the country and abroad in the event of a possible transboundary impact. Since the Chornobyl disaster, a lot of emergency exercises, research programs and projects, in particular, benchmarking, have served as international platforms for improving modeling capacity in atmospheric dispersion. This activity is carried out both on the basis of past severe accidents with significant atmospheric releases and corresponding radiological consequences, and on the basis of specific conditional (hypothetical) events that are developed in accordance with the purpose of the study. The paper is focused on the comparison results performed under the international project "Benchmarking on Assessment of Radiological COnsequences" (BARCO) conducted in 2020-2021 between five technical support organisations - members of the European Technical Safety Organisations Network (ETSON). The work contains a short overview of relevant international activity conducted in the past, a description of the BARCO project and its objectives, a list of participants, project tasks, initial data (source term, meteorology, list of benchmarking quantities, approach to data exchange, codes used). The study presents some of comparative analysis results obtained via two techniques such as code-to-code analysis (CTCA) and matched-pair analysis (MPA). The results discussion concentrates on the overall recommendations for code users. Conclusions provide the main outputs of the project.

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Learning safe practice by improving care: student-led intervention on oxygen prescribing in a respiratory ward.

BACKGROUND AND OBJECTIVE: The primary aim of this intervention was to improve oxygen prescribing in accordance with the 2008 British Thoracic Society guidelines for the prescription of emergency oxygen in adults. METHODS: Eight final year medical students reviewed the drug charts of all patients admitted to the respiratory ward on a daily basis in order to collect data on five audit questions: (1) Has oxygen (O2) been prescribed? (2) Has an O2 target saturation level been indicated? (3) Has O2 been prescribed as an 'as required' (PRN) or 'continuous therapy'? (4) Has the prescription been signed? (5) Has O2 been signed for in every drug round since the original prescription? Following an initial audit cycle an educational poster was distributed to all clinical staff via email and hard copies of the poster were placed strategically throughout the ward before its effectiveness was measured. RESULTS: During the pre-intervention phase, compliance with all five measures varied from 0 to 25%. There was an increase in the variation in compliance after the poster intervention to 14-44%; however, this masked better overall compliance with all five investigative questions with figures of 44%, 39% and 42% being recorded in three of the four post-intervention days. Overall there was increased compliance with four of the five audit questions. Indeed compliance with question 3 rose from 14% to 83%. CONCLUSIONS: The poster intervention was marginally effective while also showing that students can improve prescribing in a clinical setting.

Comparison of skin and shoe marker placement on metatarsophalangeal joint kinematics and kinetics during running.

This study investigated the effects of marker placement (skin- vs shoe-mounted) on metatarsophalangeal joint (MTP) kinematics and kinetics during running. Fifteen trained men ran on a 15-m track at 10 and 13 km/h with three (low, standard and high stiffness) shoe longitudinal bending stiffnesses (LBS). Reflective markers were fixed on the shoe upper, and on the skin using holes cut in the shoe. Three-dimensional marker positions and ground reaction forces were recorded at 200 and 2000 Hz, respectively. Kinematic and kinetic parameters were analyzed using one-dimensional metrics (statistical parametric mapping). MTP joint was less dorsiflexed at midstance ([57% to 100%] of braking phase and [0% to 48%] of pushing phase), and the MTP joint plantarflexion moment was higher ([22% to 55%] of pushing phase) with the shoe markerset in comparison with the skin markerset. The effect of LBS on MTP angle was found to be significant for a larger percentage of each stride using the shoe markerset compared to the skin markerset. However, the effect of LBS on plantarflexion moment was significant with the shoe markerset only. The effect of running speed on MTP angle was significant for a larger percentage of each stride with the skin markerset. This study demonstrates that the placement of markers influences the measurement of MTP kinematics and kinetics and that these effects are mediated by other variables such as LBS or running speed. It is concluded that the shoe markerset does not fully reflect the movement of the MTP joint.

A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma.

BACKGROUND: This study explored the efficacy and safety of rituximab as treatment of clinical or molecular residual disease after autologous stem-cell transplantation (ASCT) in follicular lymphoma (FL). PATIENTS AND METHODS: Forty patients with CD20+ FL and clinically (group A, n = 14) or clono-specific PCR-detectable (group B, n = 25) residual disease persisting 3 months after ASCT received rituximab 375 mg/m² once weekly for 4 weeks. RESULTS: Response rate at day 50 was 36% [90% confidence interval (CI) 15-61] in group A (World Health Organization criteria) and 52% (90% CI 34-70) in group B (conversion PCR-undetectable status to undetectable status). The best response rate was 71% [nine complete responses (CRs) and one partial response] in group A and 76% in group B. At 36 months, all 10 responses persisted in group A, whereas 46% of patients in group B still had PCR-undetectable disease. Furthermore, 68% of patients in group B were still in clinical CR. Rituximab after ASCT was safe with few grade 3-4 toxic effects (15% patients), mainly acute reactions and infections. CONCLUSION: Rituximab induced a high rate of durable CRs in patients with clinically detectable disease, as well as durable eradication of PCR-detectable disease in patients with FL after ASCT. Continued molecular responses assessed with a highly sensitive and clono-specific PCR technique were correlated with an excellent disease control.

Facilitating grant proposal writing in health behaviors for university faculty: a descriptive study.

Grant proposal writing in the behavioral sciences is important for fiscal reasons and scientific reasons at many universities. This report describes a grant proposal-writing seminar series provided to University faculty (N = 20) and explores factors facilitating and impeding writing. Summary statistics are provided for quantitative data. Free responses were sorted by independent raters into meaningful categories. As a consequence of the training, 45% planned to submit within 18 months; 80% of grant proposals targeted NIH. At 1-year follow-up, 40% actually submitted grants. Factors impeding grant proposal writing included competing professional demands; factors facilitating writing included regularly scheduled feedback on written proposal sections and access to expert collaborators. Obtaining grants generates financial resources, facilitates training experiences, and vastly contributes to the growth and dissemination of the knowledge base in an area.

RF generation using a compact bench gyromagnetic line.

The search for new technologies aiming to reach radiofrequency (RF) generation in different manners for diverse ends is a constant demand for several applications. The goal is to develop cost-effective and simpler systems compared to those that already exist. Our motivation is to reach an alternative way of generating RF in pulsed transmission systems employing a gyromagnetic nonlinear transmission line (GNLTL). The GNLTL consists of a ferrite-loaded-coaxial transmission line and can produce a large frequency spectrum with RF conversion efficiency above 10% from about 200 MHz up to the frequency of 2-4 GHz (S-band) for potential space-based applications. In a GNLTL, the signal amplitude is related to its propagation velocity since the peak voltage travels faster than its portion of lower amplitudes since the ferrite permeability decreases with the current amplitude. As the pulse crest travels faster than its valley, a time reduction happens in the output rise time, called pulse sharpening. Besides, the magnetic moments of ferrite dipoles initially aligned with the axial magnetic bias are displaced from their original position by the azimuthal field generated around the inner conductor by the current pulse, resulting in a damped precession movement. This movement happens along the line length as the current pulse propagates, inducing high-frequency oscillations. In short, the paper's goal is to present the experimental results using a 60-cm gyromagnetic line to provide RF in the GHz range using a solenoid for magnetic bias on a testing bench. Finally, the paper discusses the influence of the azimuthal and the axial magnetic fields on the output signal with the ferrite rings operating in a saturation state during the current pulse propagation.

Current progress in the development of RNAi-based therapeutics for HIV-1.

Highly active antiretroviral therapy (HAART) treatment for HIV has changed the course of AIDS in societies in which the drugs are readily available. Despite the great success of HAART, drug resistance and toxicity issues still remain a concern for some individuals. Thus, a number of investigators have been exploring other approaches for inhibiting HIV-1 replication. One of the most potent of these is the use of RNA interference (RNAi). This review will focus solely on the use of RNAi for the treatment of HIV-1 infection, including the problems, progress and future prospects.

Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib.

BACKGROUND: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.

Incipient allochronic speciation in the pine processionary moth (Thaumetopoea pityocampa, Lepidoptera, Notodontidae).

A plausible case of allochronic differentiation, where barrier to gene flow is primarily attributable to a phenological shift, was recently discovered in Portugal for the pine processionary moth Thaumetopoea pityocampa. Previous results suggested that the observed 'summer population' (SP) originated from the sympatric winter population (WP). Our objectives were to finely analyse these patterns and test their stability in time, through field monitoring and genetic analyses of larvae and adults across different years. Reproductive activity never overlapped between SP and WP. Microsatellites showed a clear differentiation of the SP, consistent with a strong reduction in gene flow owing to the phenological shift. Assignment tests suggested that some individuals shift from the SP to the WP phenology, causing some hybridization. We discuss these patterns and their maintenance over time. This could be a first stage of allochronic speciation, and SP should be considered as a distinct phenological race.

Climate change impact on the potential geographical distribution of two invading Xylosandrus ambrosia beetles.

Xylosandrus compactus and X. crassiusculus are two polyphagous ambrosia beetles originating from Asia and invasive in circumtropical regions worldwide. Both species were recently reported in Italy and further invaded several other European countries in the following years. We used the MaxEnt algorithm to estimate the suitable areas worldwide for both species under the current climate. We also made future projections for years 2050 and 2070 using 11 different General Circulation Models, for 4 Representative Concentration Pathways (2.6, 4.5, 6.0 and 8.5). Our analyses showed that X. compactus has not been reported in all potentially suitable areas yet. Its current distribution in Europe is localised, whereas our results predicted that most of the periphery of the Mediterranean Sea and most of the Atlantic coast of France could be suitable. Outside Europe, our results also predicted Central America, all islands in Southeast Asia and some Oceanian coasts as suitable. Even though our results when modelling its potential distribution under future climates were more variable, the models predicted an increase in suitability poleward and more uncertainty in the circumtropical regions. For X. crassiusculus, the same method only yielded poor results, and the models thus could not be used for predictions. We discuss here these results and propose advice about risk prevention and invasion management of both species.

Cost-effectiveness of Artificial Intelligence for Proximal Caries Detection.

Artificial intelligence (AI) can assist dentists in image assessment, for example, caries detection. The wider health and cost impact of employing AI for dental diagnostics has not yet been evaluated. We compared the cost-effectiveness of proximal caries detection on bitewing radiographs with versus without AI. U-Net, a fully convolutional neural network, had been trained, validated, and tested on 3,293, 252, and 141 bitewing radiographs, respectively, on which 4 experienced dentists had marked carious lesions (reference test). Lesions were stratified for initial lesions (E1/E2/D1, presumed noncavitated, receiving caries infiltration if detected) and advanced lesions (D2/D3, presumed cavitated, receiving restorative care if detected). A Markov model was used to simulate the consequences of true- and false-positive and true- and false-negative detections, as well as the subsequent decisions over the lifetime of patients. A German mixed-payers perspective was adopted. Our health outcome was tooth retention years. Costs were measured in 2020 euro. Monte-Carlo microsimulations and univariate and probabilistic sensitivity analyses were conducted. The incremental cost-effectiveness ratio (ICER) and the cost-effectiveness acceptability at different willingness-to-pay thresholds were quantified. AI showed an accuracy of 0.80; dentists' mean accuracy was significantly lower at 0.71 (minimum-maximum: 0.61-0.78, P < 0.05). AI was significantly more sensitive than dentists (0.75 vs. 0.36 [0.19-0.65]; P = 0.006), while its specificity was not significantly lower (0.83 vs. 0.91 [0.69-0.98]; P > 0.05). In the base-case scenario, AI was more effective (tooth retention for a mean 64 [2.5%-97.5%: 61-65] y) and less costly (298 [244-367] euro) than assessment without AI (62 [59-64] y; 322 [257-394] euro). The ICER was -13.9 euro/y (i.e., AI saved money at higher effectiveness). In the majority (>77%) of all cases, AI was less costly and more effective. Applying AI for caries detection is likely to be cost-effective, mainly as fewer lesions remain undetected. Notably, this cost-effectiveness requires dentists to manage detected early lesions nonrestoratively.

Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo.

Highly active antiretroviral therapy has greatly reduced the morbidity and mortality from human immunodeficiency virus (HIV) infection, but AIDS continues to be a serious health problem worldwide. Despite enormous efforts to develop a vaccine, there is still no cure, and alternative approaches including gene therapy should be explored. In this study we developed and compared combinatorial foamy virus (FV) anti-HIV vectors that also express a mutant methylguanine methyltransferase (MGMTP140K) transgene to increase the percentage of gene-modified cells after transplantation. These FV vectors inhibit replication of HIV-1 and also the simian immunodeficiency virus/HIV-1 (SHIV) chimera that can be used in monkey AIDS gene therapy studies. We identified a combinatorial FV vector that expresses 3 anti-HIV transgenes and inhibits viral replication by over 4 logs in a viral challenge assay. This FV anti-HIV vector expresses an HIV fusion inhibitor and two short hairpin RNAs (shRNAs) targeted to HIV-1 tat and rev, and can be produced at high titer (3.8 x 10(7) transducing units ml(-1)) using improved helper plasmids suitable for clinical use. Using a competitive repopulation assay, we show that human CD34(+) cells transduced with this combinatorial FV vector efficiently engraft in a mouse xenotransplantation model, and that the percentage of transduced repopulating cells can be increased after transplantation.