Thalamus is a common locus of reading, arithmetic, and IQ: Analysis of local intrinsic functional properties.

Neuroimaging studies of basic achievement skills - reading and arithmetic - often control for the effect of IQ to identify unique neural correlates of each skill. This may underestimate possible effects of common factors between achievement and IQ measures on neuroimaging results. Here, we simultaneously examined achievement (reading and arithmetic) and IQ measures in young adults, aiming to identify MRI correlates of their common factors. Resting-state fMRI (rs-fMRI) data were analyzed using two metrics assessing local intrinsic functional properties; regional homogeneity (ReHo) and fractional amplitude low frequency fluctuation (fALFF), measuring local intrinsic functional connectivity and intrinsic functional activity, respectively. ReHo highlighted the thalamus/pulvinar (a subcortical region implied for selective attention) as a common locus for both achievement skills and IQ. More specifically, the higher the ReHo values, the lower the achievement and IQ scores. For fALFF, the left superior parietal lobule, part of the dorsal attention network, was positively associated with reading and IQ. Collectively, our results highlight attention-related regions, particularly the thalamus/pulvinar as a key region related to individual differences in performance on all the three measures. ReHo in the thalamus/pulvinar may serve as a tool to examine brain mechanisms underlying a comorbidity of reading and arithmetic difficulties, which could co-occur with weakness in general intellectual abilities.

Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor.

Human muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptors compared to M3 receptors leads to subtype selectivity of AF-DX 384.

Population-based seroprevalence of Puumala hantavirus in Finland: smoking as a risk factor.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in humans, that is an endemic disease in Finland. We estimated the seroprevalence of PUUV in Finland and explored risk factors and disease associations by using unique survey data with health register linkage. A total of 2000 sera from a nationwide health survey from 2011, representative of the adult population, were screened for PUUV IgG by immunofluorescence assay. We performed statistical analysis adjusting for stratified cluster design and taking into account sampling weights. In total, 254 sera among 2000 tested were PUUV-IgG-positive resulting in a weighted seroprevalence of 12.5%, (95% CI 10.9-14.4), mirroring known age and regional variation in reported incidence. No associations between PUUV-seropositivity and chronic diseases including cardiovascular (including hypertension), pulmonary, kidney disease and cancer were observed. Smoking was significantly associated with seropositivity (adjusted OR 1.54; 95% CI 1.16-2.04). In addition, significant dose-response relations were found for the number of cigarettes smoked daily (OR 1.14; 95% CI 1.12-1.28). The results are important for disease burden assessment and guide intervention strategies, highlighting also the role of smoking prevention.

Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA.

Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate. Comparisons among these OX2R structures in complex with selective antagonists and previously determined OX1R/OX2R structures bound to non-selective antagonists revealed that the residue at positions 2.61 and 3.33 were critical for the antagonist selectivity in OX2R. The importance of these residues for binding selectivity to OX2R was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors.

Differential contributions of the middle frontal gyrus functional connectivity to literacy and numeracy.

Literacy and numeracy equally affect an individual's success in and beyond schools, but these two competencies tend to be separately examined, particularly in neuroimaging studies. The current resting-state fMRI study examined the neural correlates of literacy and numeracy in the same sample of healthy adults. We first used an exploratory "Multivariate Distance Matrix Regression" (MDMR) approach to examine intrinsic functional connectivity (iFC), highlighting the middle frontal gyrus (MFG) for both competencies. Notably, there was a hemispheric asymmetry in the MDMR-based MFG findings, with literacy associated with the left MFG, whereas numeracy associated with the right MFG (R.MFG). Results of post-hoc seed-based correlation analyses further strengthened differential contributions of MFG connections to each competency. One of the most striking and novel findings from the present work was that numeracy was negatively related to R.MFG connections with the default network, which has been largely overlooked in the literature. Our results are largely consistent with prior neuroimaging work showing distinct neural mechanisms underlying literacy and numeracy, and also indicate potentially common iFC profiles to both competencies (e.g., R.MFG with cerebellum). Taken together, our iFC findings have a potential to provide novel insights into neural bases of literacy, numeracy, and impairments in these competencies.

A Modulatory Effect of Brief Passive Exposure to Non-linguistic Sounds on Intrinsic Functional Connectivity: Relevance to Cognitive Performance.

A growing literature on resting-state fMRI (R-fMRI) has explored the impact of preceding sensory experience on intrinsic functional connectivity (iFC). However, it remains largely unknown how passive exposure to irrelevant auditory stimuli, which is a constant in everyday life, reconfigures iFC. Here, we directly compared pre- and post-exposure R-fMRI scans to examine: 1) modulatory effects of brief passive exposure to repeating non-linguistic sounds on subsequent iFC, and 2) associations between iFC modulations and cognitive abilities. We used an exploratory regional homogeneity (ReHo) approach that indexes local iFC, and performed a linear mixed-effects modeling analysis. A modulatory effect (increase) in ReHo was observed in the right superior parietal lobule (R.SPL) within the parietal attention network. Post hoc seed-based correlation analyses provided further evidence for increased parietal iFC (e.g., R.SPL with the right inferior parietal lobule). Notably, less iFC modulation was associated with better cognitive performance (e.g., word reading). These results suggest that: 1) the parietal attention network dynamically reconfigures its iFC in response to passive (thus irrelevant) non-linguistic sounds, but also 2) minimization of iFC modulation in the same network characterizes better cognitive performance. Our findings may open up new avenues for investigating cognitive disorders that involve impaired sensory processing.

The adolescent brain at risk for substance use disorders: a review of functional MRI research on motor response inhibition.

Youth with family history (FH+) of substance use disorders (SUDs) are at increased risk for developing SUDs. Similarly, childhood attention deficit hyperactivity disorder (ADHD) is considered to be a risk factor for developing SUDs. Recent research has suggested a close association between SUDs and impaired inhibitory control. As such, it is crucial to examine common and distinct neural alterations associated with inhibitory control in these at-risk groups, particularly prior to the initiation of heavy substance use. This paper reviews the functional magnetic resonance imaging (fMRI) literature of inhibitory control in these two at-risk youth populations (FH+ and ADHD), specifically considering studies that used motor response inhibition tasks (Go/No-Go or Stop Signal). Across the selected fMRI studies, we discovered no common alteration in the at-risk groups, but found neural alterations specific to each at-risk group. In FH+ youth and youth who transitioned into heavy substance use, blunted activation in the lateral part of the frontal pole (FP-lat) was most reliably observed. Importantly, longitudinal studies indicate that the blunted FP-lat activation may predict later SUDs, irrespective of the presence of FH+. In regards to ADHD, blunted activation was observed in the right dorsal anterior cingulate cortex (dACC) and left caudate. Of note, similar blunted dACC activation was also reported by one FH+ study, and thus, we cannot preclude a possibility that the right dACC activity may be a potential common alteration in both at-risk groups, particularly given a limited number of FH+ studies in the current review. Research challenges remain, and large-scale, longitudinal efforts will help determine the neurobiological markers predictive of SUDs among at-risk adolescents, including those with FH+, as well as those with ADHD and other psychiatric disorders.

Imaging the "At-Risk" Brain: Future Directions.

OBJECTIVES: Clinical neuroscience is increasingly turning to imaging the human brain for answers to a range of questions and challenges. To date, the majority of studies have focused on the neural basis of current psychiatric symptoms, which can facilitate the identification of neurobiological markers for diagnosis. However, the increasing availability and feasibility of using imaging modalities, such as diffusion imaging and resting-state fMRI, enable longitudinal mapping of brain development. This shift in the field is opening the possibility of identifying predictive markers of risk or prognosis, and also represents a critical missing element for efforts to promote personalized or individualized medicine in psychiatry (i.e., stratified psychiatry). METHODS: The present work provides a selective review of potentially high-yield populations for longitudinal examination with MRI, based upon our understanding of risk from epidemiologic studies and initial MRI findings. RESULTS: Our discussion is organized into three topic areas: (1) practical considerations for establishing temporal precedence in psychiatric research; (2) readiness of the field for conducting longitudinal MRI, particularly for neurodevelopmental questions; and (3) illustrations of high-yield populations and time windows for examination that can be used to rapidly generate meaningful and useful data. Particular emphasis is placed on the implementation of time-appropriate, developmentally informed longitudinal designs, capable of facilitating the identification of biomarkers predictive of risk and prognosis. CONCLUSIONS: Strategic longitudinal examination of the brain at-risk has the potential to bring the concepts of early intervention and prevention to psychiatry.

ASSESSMENT OF MOLECULAR GENETIC STABILITY BETWEEN LONG-TERM CRYOPRESERVED AND TISSUE CULTURED WASABI (Wasabia japonica) PLANTS.

BACKGROUND: Maintaining the genetic integrity in long-term tissue cultured and cryopreserved plants is important for the conservation of plant genetic resources. OBJECTIVE: In this study, the genetic stability of cryopreserved wasabi shoot tips stored for 10 years at -150 degree C was visualized using Amplified Fragment Length Polymorphism (AFLP) and Methylation Sensitive Amplified Polymorphism (MSAP). MATERIALS AND METHODS: The study included plants derived from cryopreserved shoot tips after 10.5 years storage at -150 degree C (LN10yr), after 2 h storage at -196 degree C (LN2hr), cryopreservation controls (No LN cooling (TC)) and non-treated controls without LN cooling (LC). The donor plants for LN2hr, TC and LC were also maintained in vitro at 20 degree C for the same period. RESULTS: Neither technique detected genetic variations in either control or cryopreserved plants. Some mutations were noted in plants maintained in tissue culture for 10 years. Comparison of genome stability for TC and LN2hr plants showed only a minor change in DNA. However, when comparing the LC and Ln10yr, many differences were found. CONCLUSION: We conclude that cryopreservation is a superior conservation method compared to tissue culture in maintaining genetic stability for a long-term storage of wasabi germplasm.

Intrinsic brain indices of verbal working memory capacity in children and adolescents.

Working memory (WM) is central to the acquisition of knowledge and skills throughout childhood and adolescence. While numerous behavioral and task-based functional magnetic resonance imaging (fMRI) studies have examined WM development, few have used resting-state fMRI (R-fMRI). Here, we present a systematic R-fMRI examination of age-related differences in the neural indices of verbal WM performance in a cross-sectional pediatric sample (ages: 7-17; n=68), using data-driven approaches. Verbal WM capacity was measured with the digit span task, a commonly used educational and clinical assessment. We found distinct neural indices of digit span forward (DSF) and backward (DSB) performance, reflecting their unique neuropsychological demands. Regardless of age, DSB performance was related to intrinsic properties of brain areas previously implicated in attention and cognitive control, while DSF performance was related to areas less commonly implicated in verbal WM storage (precuneus, lateral visual areas). From a developmental perspective, DSF exhibited more robust age-related differences in brain-behavior relationships than DSB, and implicated a broader range of networks (ventral attention, default, somatomotor, limbic networks)--including a number of regions not commonly associated with verbal WM (angular gyrus, subcallosum). These results highlight the importance of examining the neurodevelopment of verbal WM and of considering regions beyond the "usual suspects".

Cortical thickness abnormalities associated with dyslexia, independent of remediation status.

Abnormalities in cortical structure are commonly observed in children with dyslexia in key regions of the "reading network." Whether alteration in cortical features reflects pathology inherent to dyslexia or environmental influence (e.g., impoverished reading experience) remains unclear. To address this question, we compared MRI-derived metrics of cortical thickness (CT), surface area (SA), gray matter volume (GMV), and their lateralization across three different groups of children with a historical diagnosis of dyslexia, who varied in current reading level. We compared three dyslexia subgroups with: (1) persistent reading and spelling impairment; (2) remediated reading impairment (normal reading scores), and (3) remediated reading and spelling impairments (normal reading and spelling scores); and a control group of (4) typically developing children. All groups were matched for age, gender, handedness, and IQ. We hypothesized that the dyslexia group would show cortical abnormalities in regions of the reading network relative to controls, irrespective of remediation status. Such a finding would support that cortical abnormalities are inherent to dyslexia and are not a consequence of abnormal reading experience. Results revealed increased CT of the left fusiform gyrus in the dyslexia group relative to controls. Similarly, the dyslexia group showed CT increase of the right superior temporal gyrus, extending into the planum temporale, which resulted in a rightward CT asymmetry on lateralization indices. There were no group differences in SA, GMV, or their lateralization. These findings held true regardless of remediation status. Each reading level group showed the same "double hit" of atypically increased left fusiform CT and rightward superior temporal CT asymmetry. Thus, findings provide evidence that a developmental history of dyslexia is associated with CT abnormalities, independent of remediation status.

A cross-linguistic evaluation of script-specific effects on fMRI lateralization in late second language readers.

Behavioral and neuroimaging studies have provided evidence that reading is strongly left lateralized, and the degree of this pattern of functional lateralization can be indicative of reading competence. However, it remains unclear whether functional lateralization differs between the first (L1) and second (L2) languages in bilingual L2 readers. This question is particularly important when the particular script, or orthography, learned by the L2 readers is markedly different from their L1 script. In this study, we quantified functional lateralization in brain regions involved in visual word recognition for participants' L1 and L2 scripts, with a particular focus on the effects of L1-L2 script differences in the visual complexity and orthographic depth of the script. Two different groups of late L2 learners participated in an fMRI experiment using a visual one-back matching task: L1 readers of Japanese who learnt to read alphabetic English and L1 readers of English who learnt to read both Japanese syllabic Kana and logographic Kanji. The results showed weaker leftward lateralization in the posterior lateral occipital complex (pLOC) for logographic Kanji compared with syllabic and alphabetic scripts in both L1 and L2 readers of Kanji. When both L1 and L2 scripts were non-logographic, where symbols are mapped onto sounds, functional lateralization did not significantly differ between L1 and L2 scripts in any region, in any group. Our findings indicate that weaker leftward lateralization for logographic reading reflects greater requirement of the right hemisphere for processing visually complex logographic Kanji symbols, irrespective of whether Kanji is the readers' L1 or L2, rather than characterizing additional cognitive efforts of L2 readers. Finally, brain-behavior analysis revealed that functional lateralization for L2 visual word processing predicted L2 reading competency.

Cerebral mechanisms for different second language writing systems.

In this fMRI study, we examined the cerebral processing associated with second language (L2) reading in different writing systems in late L2 learners. To examine the impacts of cross-linguistic differences between the first language (L1) and L2 on learning to read in L2, we employed a bidirectional approach and compared brain activation during single word processing in two groups of late L2 readers: (1) L2 readers of English whose L1 was Japanese (Japanese-L1/English-L2) and (2) L2 readers of Japanese (of syllabic Kana only) whose L1 was English (English-L1/Japanese-L2). During English reading, the L2 readers of English (Japanese-L1/English-L2) exhibited stronger activation in the left superior parietal lobule/supramarginal gyrus, relative to the L1 readers of English (English-L1/Japanese-L2). This is a region considered to be involved in phonological processing. The increased activation in the Japanese-L1/English-L2 group likely reflects the increased cognitive load associated with L2 English reading, possibly because L1 readers of Kana, which has an extremely regular orthography, may need to adjust to the greater phonological demands of the irregular L2 English orthography. In contrast, during Kana reading, the L2 readers of Japanese Kana (English-L1/Japanese-L2) exhibited stronger activation in the lingual gyrus in both the left and right hemispheres compared to the L1 readers of Kana (Japaese-L1/English-L2). This additional activation is likely to reflect the lower level of visual familiarity to the L2 symbols in the English-L1/Japanese-L2 group; Kana symbols are uniquely used only in Japan, whereas Roman alphabetic symbols are seen nearly everywhere. These findings, bolstered by significant relationships between the activation of the identified regions and cognitive competence, suggest that the cerebral mechanisms for L2 reading in late learners depends both on which language is their L1 and which language is to be learnt as their L2. Educational implications of these results are discussed.

A new protein complex promoting the assembly of Rad51 filaments.

During homologous recombination, eukaryotic RecA homologue Rad51 assembles into a nucleoprotein filament on single-stranded DNA to catalyse homologous pairing and DNA-strand exchange with a homologous template. Rad51 nucleoprotein filaments are highly dynamic and regulated via the coordinated actions of various accessory proteins including Rad51 mediators. Here, we identify a new Rad51 mediator complex. The PCSS complex, comprising budding yeast Psy3, Csm2, Shu1 and Shu2 proteins, binds to recombination sites and is required for Rad51 assembly and function during meiosis. Within the hetero-tetramer, Psy3-Csm2 constitutes a core sub-complex with DNA-binding activity. In vitro, purified Psy3-Csm2 stabilizes the Rad51-single-stranded DNA complex independently of nucleotide cofactor. The mechanism of Rad51 stabilization is inferred by our high-resolution crystal structure, which reveals Psy3-Csm2 to be a structural mimic of the Rad51-dimer, a fundamental unit of the Rad51-filament. Together, these results reveal a novel molecular mechanism for this class of Rad51-mediators, which includes the human Rad51 paralogues.

Cortical signatures of dyslexia and remediation: an intrinsic functional connectivity approach.

This observational, cross-sectional study investigates cortical signatures of developmental dyslexia, particularly from the perspective of behavioral remediation. We employed resting-state fMRI, and compared intrinsic functional connectivity (iFC) patterns of known reading regions (seeds) among three dyslexia groups characterized by (a) no remediation (current reading and spelling deficits), (b) partial remediation (only reading deficit remediated), and (c) full remediation (both reading and spelling deficits remediated), and a group of age- and IQ-matched typically developing children (TDC) (total N = 44, age range = 7-15 years). We observed significant group differences in iFC of two seeds located in the left posterior reading network - left intraparietal sulcus (L.IPS) and left fusiform gyrus (L.FFG). Specifically, iFC between L.IPS and left middle frontal gyrus was significantly weaker in all dyslexia groups, irrespective of remediation status/literacy competence, suggesting that persistent dysfunction in the fronto-parietal attention network characterizes dyslexia. Additionally, relative to both TDC and the no remediation group, the remediation groups exhibited stronger iFC between L.FFG and right middle occipital gyrus (R.MOG). The full remediation group also exhibited stronger negative iFC between the same L.FFG seed and right medial prefrontal cortex (R.MPFC), a core region of the default network These results suggest that behavioral remediation may be associated with compensatory changes anchored in L.FFG, which reflect atypically stronger coupling between posterior visual regions (L.FFG-R.MOG) and greater functional segregation between task-positive and task-negative regions (L.FFG-R.MPFC). These findings were bolstered by significant relationships between the strength of the identified functional connections and literacy scores. We conclude that examining iFC can reveal cortical signatures of dyslexia with particular promise for monitoring neural changes associated with behavioral remediation.

Medicare's national coverage determinations in diagnostic radiology: examining evidence and setting limits.

OBJECTIVE: To systematically review and summarize the Center for Medicare and Medicaid Services (CMS) national coverage determination (NCDs) pertaining diagnostic imaging technologies from 1999 through 2010. METHODS: All NCDs pertaining to diagnostic imaging were identified from the Tufts Medical Center NCD database. The variables under study included the quality of the clinical evidence and the final coverage determination. The types of restrictions were categorized. We also categorized the final decisions as "positive coverage" or "no positive/no change in coverage" and assessed the correlation between positive coverage and other variables using Fisher exact test. RESULTS: Twenty-two of 152 (15%) NCDs pertained to diagnostic imaging technologies. The supporting evidence was judge to be good, fair, and poor in 5, 6, and 11 cases, respectively. Eleven technologies (50%) were covered with conditions, four (18%) deferred the coverage decision to local level, and two (9%) were completely not covered. In five instances there was no change to the prior coverage status. Of the 11 decisions resulting in positive coverage, 8 (73%) restricted use to specific population subgroups, 5 (46%) applied restrictions related to treatment, 4 were covered with evidence development, and 2 were restricted to care in specific settings. A significantly higher rate of positive coverage decisions was achieved if the available evidence was good (100% 5/5) or fair (83% 5/6) compared to technologies with poor evidence (10% 1/10) (P < .01). CONCLUSION: CMS has demonstrated a propensity to limit the use of advanced diagnostic imaging to scenarios in which appropriateness is supported by adequate evidence of clinical utility and improved outcomes with the quality of evidence being a significant factor on final decisions. Understanding the need for high-quality evidence and the types of limitations placed on coverage allows for appropriate planning for the incorporation of diagnostic imaging technologies into clinical practice.

Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer.

BACKGROUND: In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity. METHODS: S-1 was given orally at a dose of 80 mg/m(2)/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity. RESULTS: We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1 months, and median overall survival (OS) was 11.2 months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P = 0.0288). Median PFS was 4.8 and 2.5 months (P = 0.038), and median OS was 22.4 and 8.4 months (P = 0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients. CONCLUSIONS: S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.

Resting-state functional connectivity indexes reading competence in children and adults.

Task-based neuroimaging studies face the challenge of developing tasks capable of equivalently probing reading networks across different age groups. Resting-state fMRI, which requires no specific task, circumvents these difficulties. Here, in 25 children (8-14 years) and 25 adults (21-46 years), we examined the extent to which individual differences in reading competence can be related to resting-state functional connectivity (RSFC) of regions implicated in reading. In both age groups, reading standard scores correlated positively with RSFC between the left precentral gyrus and other motor regions, and between Broca's and Wernicke's areas. This suggests that, regardless of age group, stronger coupling among motor regions, as well as between language/speech regions, subserves better reading, presumably reflecting automatized articulation. We also observed divergent RSFC-behavior relationships in children and adults, particularly those anchored in the left fusiform gyrus (FFG) (the visual word form area). In adults, but not children, better reading performance was associated with stronger positive correlations between FFG and phonology-related regions (Broca's area and the left inferior parietal lobule), and with stronger negative relationships between FFG and regions of the "task-negative" default network. These results suggest that both positive RSFC (functional coupling) between reading regions and negative RSFC (functional segregation) between a reading region and default network regions are important for automatized reading, characteristic of adult readers. Together, our task-independent RSFC findings highlight the importance of appreciating developmental changes in the neural correlates of reading competence, and suggest that RSFC may serve to facilitate the identification of reading disorders in different age groups.

Regression analysis on the variation in efficiency frontiers for prevention stage of HIV/AIDS.

OBJECTIVES: To investigate how the cost effectiveness of preventing HIV/AIDS varies across possible efficiency frontiers (EFs) by taking into account potentially relevant external factors, such as prevention stage, and how the EFs can be characterized using regression analysis given uncertainty of the QALY-cost estimates. METHODS: We reviewed cost-effectiveness estimates for the prevention and treatment of HIV/AIDS published from 2002-2007 and catalogued in the Tufts Medical Center Cost-Effectiveness Analysis (CEA) Registry. We constructed efficiency frontier (EF) curves by plotting QALYs against costs, using methods used by the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany. We stratified the QALY-cost ratios by prevention stage, country of study, and payer perspective, and estimated EF equations using log and square-root models. RESULTS: A total of 53 QALY-cost ratios were identified for HIV/AIDS in the Tufts CEA Registry. Plotted ratios stratified by prevention stage were visually grouped into a cluster consisting of primary/secondary prevention measures and a cluster consisting of tertiary measures. Correlation coefficients for each cluster were statistically significant. For each cluster, we derived two EF equations - one based on the log model, and one based on the square-root model. DISCUSSION: Our findings indicate that stratification of HIV/AIDS interventions by prevention stage can yield distinct EFs, and that the correlation and regression analyses are useful for parametrically characterizing EF equations. Our study has certain limitations, such as the small number of included articles and the potential for study populations to be non-representative of countries of interest. Nonetheless, our approach could help develop a deeper appreciation of cost effectiveness beyond the deterministic approach developed by IQWiG.

Functional MRI evidence for the importance of visual short-term memory in logographic reading.

Logographic symbols are visually complex, and thus children's abilities for visual short-term memory (VSTM) predict their reading competence in logographic systems. In the present study, we investigated the importance of VSTM in logographic reading in adults, both behaviorally and by means of fMRI. Outside the scanner, VSTM predicted logographic Kanji reading in native Japanese adults (n=45), a finding consistent with previous observations in Japanese children. In the scanner, participants (n=15) were asked to perform a visual one-back task. For this fMRI experiment, we took advantage of the unique linguistic characteristic of the Japanese writing system, whereby syllabic Kana and logographic Kanji can share the same sound and meaning, but differ only in the complexity of their visual features. Kanji elicited greater activation than Kana in the cerebellum and two regions associated with VSTM, the lateral occipital complex and the superior intraparietal sulcus, bilaterally. The same regions elicited the highest activation during the control condition (an unfamiliar, unpronounceable script to the participants), presumably due to the increased VSTM demands for processing the control script. In addition, individual differences in VSTM performance (outside the scanner) significantly predicted blood oxygen level-dependent signal changes in the identified VSTM regions, during the Kanji and control conditions, but not during the Kana condition. VSTM appears to play an important role in reading logographic words, even in skilled adults, as evidenced at the behavioral and neural level, most likely due to the increased VSTM/visual attention demands necessary for processing complex visual features inherent in logographic symbols.