Evolving Use of fMRI in Medicare Beneficiaries.

Using the Medicare Physician-Supplier Procedure Summary Master File, we evaluated the evolving use of fMRI in Medicare fee-for-service beneficiaries from 2007 through 2017. Annual use rates (per 1,000,000 enrollees) increased from 17.7 to 32.8 through 2014 and have remained static since. Radiologists have remained the dominant specialty group from 2007 to 2017 (86.4% and 88.6% of all services, respectively), and the outpatient setting has remained the dominant place of service (65.4% and 65.4%, respectively).

A new malaria vector in Africa: Predicting the expansion range of Anopheles stephensi and identifying the urban populations at risk.

In 2012, an unusual outbreak of urban malaria was reported from Djibouti City in the Horn of Africa and increasingly severe outbreaks have been reported annually ever since. Subsequent investigations discovered the presence of an Asian mosquito species; Anopheles stephensi, a species known to thrive in urban environments. Since that first report, An. stephensi has been identified in Ethiopia and Sudan, and this worrying development has prompted the World Health Organization (WHO) to publish a vector alert calling for active mosquito surveillance in the region. Using an up-to-date database of published locational records for An. stephensi across its full range (Asia, Arabian Peninsula, Horn of Africa) and a set of spatial models that identify the environmental conditions that characterize a species' preferred habitat, we provide evidence-based maps predicting the possible locations across Africa where An. stephensi could establish if allowed to spread unchecked. Unsurprisingly, due to this species' close association with man-made habitats, our maps predict a high probability of presence within many urban cities across Africa where our estimates suggest that over 126 million people reside. Our results strongly support the WHO's call for surveillance and targeted vector control and provide a basis for the prioritization of surveillance.

Effects of the spatial repellent metofluthrin on landing rates of outdoor biting anophelines in Cambodia, Southeast Asia.

The emergence of artemisinin-resistant malaria in Southeast Asia is a major problem. The fact that many people become infected with malaria when they are outside has prompted the development of 'spatial' rather than topical repellents. The respective effects of one or four slow-release emanators of metofluthrin, a pyrethroid, were tested in Pailin, Pursat and Koh Kong, Cambodia. Numbers of mosquitoes counted in outdoor landing catches when one or four emanators were suspended close to the collector were compared with control collections. In Pailin, the effects of emanators on catches in Furvela tent traps and Centers for Disease Control (CDC) light traps suspended underneath houses were also investigated. Rate ratios were used to determine differences. A total of 29 255 mosquitoes were collected over 2934 h of landing collections, 87 nights of tent trapping and 81 nights of light trap capture. In Pailin, landing rates were reduced by 48% by a single emanator and by 67% by four emanators (P < 0.001). Similar reductions were observed in the number of mosquitoes collected in tent traps and the number of anophelines only collected in light traps. Results were similar in Pursat, but, for unknown reasons, those in Koh Kong showed no difference between control and metofluthrin collections (P > 0.05). These findings suggest that although the product can produce a significant effect, it requires further improvement.

Same-Day Sinus and Brain CT Imaging in the Medicare Population: Are Practice Patterns Changing in Association with Medicare Policy Initiatives?

BACKGROUND AND PURPOSE: Monitoring the frequency of same-day sinus and brain CT (Outpatient Measure 14, "OP-14") is part of a recent large Centers for Medicare and Medicaid Services hospital outpatient quality initiative to improve imaging efficiency. This study investigates patient-level claims data in the Medicare population focusing on where same-day sinus and brain CT imaging is performed and how the frequency of same-day studies changed with time before and during OP-14 measure program implementation. MATERIALS AND METHODS: Research Identifiable Files were used to identify all sinus and brain CT examinations from 2004 through 2012 for a 5% random patient sample of Medicare fee-for-service beneficiaries. Overall and site of service use rates were calculated for same- and non-same-day examinations. Changes were mapped to policy initiative timetables. RESULTS: The number of same-day sinus and brain CT studies from 2004 to 2012 increased 67% from 1.85 (95% CI, 1.78-1.91) per 1000 Medicare beneficiaries in 2004 to 3.08 (95% CI, 3.00-3.15) in 2012. The biggest driver of increased same-day studies was the emergency department setting, from 0.56 (95% CI, 0.53-0.60) per 1000 to 1.78 (95% CI, 1.72-1.84; +215.7%). Overall use of brain CT from 146.0 (95% CI, 145.1-146.9) per 1000 to 176.3 (95% CI, 175.4-177.2; +21%) and sinus CT from 12.6 (95% CI, 12.4-12.8) per 1000 to 15.4 (95% CI, 15.2-15.6; +22%) increased until 2009 and remained stable through 2012. CONCLUSIONS: Previously increasing same-day sinus and brain CT in Medicare beneficiaries plateaued in 2009, coinciding with the implementation of targeted measures by the Centers for Medicare and Medicaid Services. Same-day imaging continues to increase in the emergency department setting.

Differential transcription profiles in Aedes aegypti detoxification genes after temephos selection.

The mosquito Aedes aegypti is the main vector of Dengue and Yellow Fever flaviviruses. The organophosphate insecticide temephos is a larvicide that is used globally to control Ae. aegypti populations; many of which have in turn evolved resistance. Target site alteration in the acetylcholine esterase of this species has not being identified. Instead, we tracked changes in transcription of metabolic detoxification genes using the Ae. aegypti 'Detox Chip' microarray during five generations of temephos selection. We selected for temephos resistance in three replicates in each of six collections, five from Mexico, and one from Peru. The response to selection was tracked in terms of lethal concentrations. Uniform upregulation was seen in the epsilon class glutathione-S-transferase (eGST) genes in strains from Mexico prior to laboratory selection, while eGSTs in the Iquitos Peru strain became upregulated after five generations of temephos selection. While expression of many carboxyl/cholinesterase esterase (CCE) genes increased with selection, no single esterase was consistently upregulated and this same pattern was noted in the cytochrome P450 monooxygenase (CYP) genes and in other genes involved in reduction or oxidation of xenobiotics. Bioassays using glutathione-S-transferase (GST), CCE and CYP inhibitors suggest that various CCEs instead of GSTs are the main metabolic mechanism conferring resistance to temephos. We show that temephos-selected strains show no cross resistance to permethrin and that genes associated with temephos selection are largely independent of those selected with permethrin in a previous study.

Transcription of detoxification genes after permethrin selection in the mosquito Aedes aegypti.

Changes in gene expression before, during and after five generations of permethrin laboratory selection were monitored in six strains of Aedes aegypti: five F(2)-F(3) collections from the Yucatán Peninsula of Mexico and one F(2) from Iquitos, Peru. Three biological replicate lines were generated for each strain. The response to selection was measured as changes in the lethal and knockdown permethrin concentrations (LC(50), KC(50)) and in the frequency of the Ile1,016 substitution in the voltage-gated sodium channel (para) gene. Changes in expression of 290 metabolic detoxification genes were measured using the 'Aedes Detox' microarray. Selection simultaneously increased the LC(50), KC(50) and Ile1,016 frequency. There was an inverse relationship between Ile1,016 frequency and the numbers of differentially transcribed genes. The Iquitos strain lacked the Ile1,016 allele and 51 genes were differentially transcribed after selection as compared with 10-18 genes in the Mexican strains. Very few of the same genes were differentially transcribed among field strains but 10 cytochrome P(450) genes were upregulated in more than one strain. Laboratory adaptation to permethrin in Ae. aegypti is genetically complex and largely conditioned by geographic origin and pre-existing target site insensitivity in the para gene. The lack of uniformity in the genes that responded to artificial selection as well as differences in the direction of their responses challenges the assumption that one or a few genes control permethrin metabolic resistance. Attempts to identify one or a few metabolic genes that are predictably associated with permethrin adaptation may be futile.

Orexinergic neuron numbers in three species of African mole rats with rhythmic and arrhythmic chronotypes.

In the present study, orexinergic cell bodies within the brains of rhythmic and arrhythmic circadian chronotypes from three species of African mole rat (Highveld mole rat-Cryptomys hottentotus pretoriae, Ansell's mole rat--Fukomys anselli and the Damaraland mole rat--Fukomys damarensis) were identified using immunohistochemistry for orexin-A. Immunopositive orexinergic (Orx+) cell bodies were stereologically assessed and absolute numbers of orexinergic cell bodies were determined for the distinct circadian chronotypes of each species of mole rat examined. The aim of the study was to investigate whether the absolute numbers of identified orexinergic neurons differs between distinct circadian chronotypes with the hypothesis of elevated hypothalamic orexinergic neurons in the arrhythmic chronotypes compared with the rhythmic chronotypes. We found statistically significant differences between the circadian chronotypes ofF. anselli, where the arrhythmic group had higher mean numbers of hypothalamic orexin neurons compared with the rhythmic group. These differences were observed when the raw data was compared and when the raw data was corrected for body mass (M(b)) and brain mass (M(br)). For the two other species investigated, no significant differences were noted between the chronotypes, although a statistically significant difference was noted between all rhythmic and arrhythmic individuals of the current study when the counts of orexin neurons were corrected for M(b)--the arrhythmic individuals had larger numbers of orexin cells.

Effects of seasonality and irrigation on malaria transmission in two villages in Côte d'Ivoire.

The seasonality of malaria transmission was investigated in two villages in central Côte d'Ivoire: one usually with irrigated rice farming (Zatta) and one without (Tiémélékro). Adult mosquitoes were collected, from February 2002 to August 2005, inside and outside sentinel houses. In Tiémélékro, the biting rate of Anopheles gambiae s.s. showed a significant difference between the dry and rainy season only in 2003 (P<0.001). The corresponding rates for An. funestus s.s. showed significant seasonal differences in both 2002 and 2003 (P<0.001 for each year). In Zatta in 2003-2004, when irrigated rice farming was interrupted, there was no significant difference between the An. gambiae s.s. biting rates recorded in the dry and rainy seasons. In both 2002 and 2005, however, when irrigated rice farming was practised, the An. gambiae s.s. biting rate recorded in Zatta during the rainy season was significantly higher than that seen in the dry season (P<0.001 for each year). With just one exception (in Tiémélékro in 2005, the prevalence of Plasmodium infection in the An. funestus was significantly higher in the rainy season than in the dry season), no significant seasonal differences were seen in the prevalences of Plasmodium infection among the An. gambiae or An. funestus. In conclusion, although malaria transmission is quite stable in central Côte d'Ivoire throughout the year, it can be distinctly modified by irrigated rice farming.

Cross-sectional area of the elephant corpus callosum: comparison to other eutherian mammals.

The current study reports our findings of the relationship between cross-sectional area of the corpus callosum and brain mass in over 100 eutherian mammal species. We were specifically interested in determining whether the elephant had a corpus callosum the size that would be expected for eutherian mammal with a brain mass of approximately 5000 g, or whether a different morphology had evolved. To answer this question we first analysed data from primates, other eutherian mammals and cetaceans, finding that primates and other eutherian mammals showed a positive allometric relationship between the two variables, such that larger brains had a relatively larger corpus callosum. Interestingly, primates have a slightly larger corpus callosum than other eutherian mammals, but showed a similar allometric scaling to this group. The cetaceans had a both absolutely and relatively small corpus callosum compared to other mammals and showed isometric scaling with brain mass. The six elephants studied herein had the largest absolute corpus callosums recorded to date; however, relative to the mass of their brain, the size of the corpus callosum was what would be expected of a typical eutherian mammal with a brain mass of approximately 5000 g. The data for elephants hinted at sexual dimorphism in size of the corpus callosum, with female elephants having both an absolute and relatively larger callosum than the males. If this observation is supported in future studies, the elephants will be the first non-primate species to show sexual dimorphism in this neural character. The results are discussed in both an evolutionary and functional context.

Malaria management: past, present, and future.

The prospect of malaria eradication has been raised recently by the Bill and Melinda Gates Foundation with support from the international community. There are significant lessons to be learned from the major successes and failures of the eradication campaign of the 1960s, but cessation of transmission in the malaria heartlands of Africa will depend on a vaccine and better drugs and insecticides. Insect control is an essential part of reducing transmission. To date, two operational scale interventions, indoor residual spraying and deployment of long-lasting insecticide-treated nets (LLINs), are effective at reducing transmission. Our ability to monitor and evaluate these interventions needs to be improved so that scarce resources can be sensibly deployed, and new interventions that reduce transmission in a cost-effective and efficient manner need to be developed. New interventions could include using transgenic mosquitoes, larviciding in urban areas, or utilizing cost-effective consumer products. Alongside this innovative development agenda, the potential negative impact of insecticide resistance, particularly on LLINs, for which only pyrethroids are available, needs to be monitored.

Propetamphos resistance in Rhipicephalus bursa (Acari, Ixodidae).

Hard tick infestation is an important problem in both traditional and industrial animal husbandry as well as in veterinary and public health. Several acaricides have been used to control tick infestation in Iran. Poor control has been attributed to acaricide resistance in tick populations although this has not been demonstrated experimentally. In this study, susceptibility status to propetamphos (Blotic) of 2-3-week-old larvae of Rhipicephalus bursa, one of the most common tick species in Iran, was evaluated using the FAO recommended larval packet test (LPT) method with some modifications. Log dosage probit analysis of propetamphos dose-response regression lines produced a resistance ratio based on LC(50) in the most resistant strain of approximately 103-fold. Biochemical assays suggested that the tick strains contained multiple insecticide resistance mechanisms involving elevation of esterases, GSTs, MFOs and alteration of acetylcholinesterase. In light of this data, practical implications for pest and pesticide resistance management strategies are discussed.

Mosquitoes and bednets: testing the spatial positioning of insecticide on nets and the rationale behind combination insecticide treatments.

The recent development of pyrethroid resistance of operational significance in Anopheles gambiae s.l. is a major threat to the control of malaria in West Africa. The so-called '2-in-1' bednet, in which the top of the net is treated with a non-pyrethroid insecticide and the sides with pyrethroid, has been proposed as a way of maintaining efficacy in the wake of such resistance. A host-seeking female Anopheles mosquito must contact both the top and sides of a '2-in-1' net, however, for such nets to be useful in resistance management. In the present study, the interaction between mosquitoes and insecticide-treated bednets (ITN) was explored by restricting the insecticide to particular surfaces of the nets (top only or sides only) and then testing these nets, untreated nets and nets treated on all their surfaces in experimental huts, under simulated field conditions. Over the 6-week trial, there was no significant difference in An. arabiensis mortality between nets treated with pyrethroid on the top only (39.2%), sides only (39.6%) and all surfaces (39.7%), thus indicating that a female An. arabiensis usually contacts both the top and sides of a bednet during its host-seeking behaviour. The data on blood-feeding indicated, however, that the insecticide used on the sides of the net may be more important in preventing mosquito biting than that on the top. These results support the rationale behind the '2-in-1' nets. Such nets may have advantages over the use of nets treated on all surfaces with a mixture of insecticides that includes a non-pyrethroid component. With the '2-in-1', the more toxic component can be deployed on the top of the net, away from human contact, while the more repellent pyrethroid can be restricted to the sides, to prevent blood-feeding. With the scaling-up of ITN coverage and the need to preserve pyrethroid efficacy, more consideration should be given to switching from pyrethroid-only nets to 'combination' nets that have been treated with a pyrethroid and another insecticide. Since the mosquitoes that act as malarial vectors may contact all surfaces of a bednet during their host-seeking, spatial heterogeneity in insecticide levels over the surface of a net may not reduce that net's overall efficacy. Nets with a rather uneven distribution of insecticide (such as those that might be produced using home-treatment insecticide kits) may therefore be no less effective, prior to washing, than nets with a more even distribution of insecticide (such as long-lasting insecticidal nets produced under factory conditions).

Operational impact of DDT reintroduction for malaria control on Anopheles arabiensis in Mozambique.

ABSTRACT With the increase in indoor residual spraying in many internationally and nationally funded malaria control programs, and affirmation by World Health Organization (WHO) that DDT is appropriate for use in the absence of longer lasting insecticide formulations in some malaria endemic settings, DDT has been reintroduced as a major malaria control intervention in Africa. Indoor residual spraying with DDT was reintroduced into Mozambique for malaria control in 2005, and it is increasingly becoming the main insecticide used for malaria vector control in Mozambique. The selection of DDT in Mozambique is evidence-based, taking account of the susceptibility of Anopheles arabiensis (Patton) and Anopheles gambiae (Giles) s.s. to all the available insecticide choices, as well as relative costs of the insecticide and the logistical costs of spraying. Before this time in Mozambique, DDT was replaced by h-cyhalothrin in 1993. Resistance occurred quickly to this insecticide, and in 2000 the pyrethroid was phased out and the carbamate bendiocarb was introduced. Low-level resistance was detected by biochemical assay to bendiocarb in 1999 in both Anopheles funestus (Giles) and An. arabiensis, although this was not evident in WHO bioassays of the same population. In the 2000-2006 surveys the levels of bendiocarb resistance had been selected to a higher level in An. arabiensis, with resistance detectable by both biochemical and WHO bioassay. The insecticide resistance monitoring program includes assessment of field populations by standard WHO insecticide susceptibility assays and biochemical assays. Monitoring was established in 1999, and it was maintained as part of an operational monitoring and evaluation program thereafter.

Pristinamycin as adjunctive therapy in the management of Gram-positive multi-drug resistant organism (MDRO) osteoarticular infection.

OBJECTIVE: Osteoarticular infection often requires prolonged antibiotic therapy as an adjunct to surgery. We report our experience using pristinamycin, an oral streptogramin, when conventional antibiotics were poorly tolerated or inappropriate because of multi-drug resistant organisms (MDROs). METHODS: We retrospectively identified, from pharmacy records, all patients prescribed pristinamycin between 1/1/2004 and 31/12/2006. We collected clinical and microbiological data. RESULTS: Twenty-one patients were identified (13 male and eight female patients, age range 18-83 years). Sixteen patients (76%) had infection due to MDROs and five (24%) were intolerant of conventional antibiotics. Ten patients received other concurrent oral antibiotics. Eleven of 21 (52%) patients remained free of recurrent infection off antibiotics at a mean follow up duration of 13 months, (range 4-25 months). Suppression of infection while still on therapy was achieved in a further four patients (19%) with a mean follow up of 11.5 months (range 5-15 months). Six patients (29%) failed therapy, all requiring a further surgical procedure. CONCLUSION: Oral pristinamycin was a well tolerated and useful adjunctive treatment in this group with complex orthopaedic infection. Pristinamycin can be considered in patients with osteoarticular infection due to Gram-positive organisms when antibiotic multi-resistance or intolerance makes conventional therapies impossible. SUMMARY: We report our experiences of using pristinamycin in the management of 21 patients with Gram-positive MDRO osteoarticular infection or who were unable to tolerate more conventional regimens. Our results show that pristinamycin is well tolerated with outcomes comparable to those of other agents described in the literature on osteoarticular infection.

Characterization of inhibitors and substrates of Anopheles gambiae CYP6Z2.

Three CYP6Z genes are linked to a major pyrethroid resistance locus in the mosquito Anopheles gambiae. We have expressed CYP6Z2 in Escherichia coli and produced a structural model in order to examine its role in detoxification. E. coli membranes co-expressing CYP6Z2 and An. gambiae P450 reductase (AgCPR) catalysed the dealkylation of benzyloxyresorufin with kinetic parameters K(m) = 0.13 microM; K(cat) = 1.5 min(-1). The IC(50) values of a wide range of compounds were measured. Pyrethroids cypermethrin and permethrin produced low IC(50) values, but were not metabolized. Plant flavanoids were the most potent inhibitors. Several compounds were shown to be substrates, suggesting that CYP6Z2 has broad substrate specificity and plays an important chemo-protective role during the herbivorous phase of the life-cycle.

A mutation in the voltage-gated sodium channel gene associated with pyrethroid resistance in Latin American Aedes aegypti.

Pyrethroids are commonly used as mosquito adulticides and evolution of resistance to these compounds is a major threat to public health. 'Knockdown resistance' to pyrethroids (kdr) is frequently caused by nonsynonymous mutations in the voltage-gated sodium channel transmembrane protein (para) that reduce pyrethroid binding. Early detection of kdr is critical to the development of resistance management strategies in mosquitoes including Aedes aegypti, the most prevalent vector of dengue and yellow fever viruses. Brengues et al. described seven novel mutations in hydrophobic segment 6 of domain II of para in Ae. aegypti. Assays on larvae from strains bearing these mutations indicated reduced nerve sensitivity to permethrin inhibition. Two of these occurred in codons Iso1011 and Val1016 in exons 20 and 21 respectively. A transition in the third position of Iso1011 encoded a Met1011 replacement and a transversion in the second position of Val1016 encoded a Gly1016 replacement. We have screened this same region in 1318 mosquitoes in 32 additional strains; 30 from throughout Latin America. While the Gly1016 allele was never detected in Latin America, we found two new mutations in these same codons. A transition in the first position of codon 1011 encodes a Val replacement while a transition in the first position of codon 1016 encodes an Iso replacement. We developed PCR assays for these four mutations that can be read either on an agarose gel or as a melting curve. Selection experiments, one with deltamethrin on a field strain from Santiago de Cuba and another with permethrin on a strain from Isla Mujeres, Mexico rapidly increased the frequency of the Iso1016 allele. Bioassays of F(3) offspring arising from permethrin susceptible Val1016 homozygous parents and permethrin resistant Iso1016 homozygous parents show that Iso1016 segregates as a recessive allele in conferring kdr. Analysis of segregation between alleles at the 1011 and 1016 codons in the F(3) showed a high rate of recombination even though the two codons are only separated by a ~250 bp intron. The tools and information presented provide a means for early detection and characterization of kdr that is critical to the development of strategies for resistance management.

Transcriptional analysis of insecticide resistance in Anopheles stephensi using cross-species microarray hybridization.

A large scale microarray (20k MMC1) from the African malaria vector Anopheles gambiae was used to monitor gene expression in insecticide resistant and susceptible strains of the Asian mosquito Anopheles stephensi. Heterologous hybridization at slightly reduced stringency yielded approximately 7000 significant signals. Thirty-six putative genes were differentially transcribed between the pyrethroid-resistant (DUB-R) and the susceptible (BEECH) strains. The expression profiles of selected transcripts were verified by real-time PCR. A gene putatively involved in the thickening of the adult cuticle showed the most striking up-regulation in DUB-R. A more specialized microarray containing 231 An. gambiae genes putatively involved in insecticide detoxification was used to further analyse classical insecticide resistance genes. Three glutathione S-transferase (GST) transcripts, one esterase and a cytochrome P450 were up-regulated in the resistant strain, while two peroxidases were down-regulated.