A Systematic Review of Value Criteria for Next-Generation Sequencing/Comprehensive Genomic Profiling to Inform Value Framework Development.

OBJECTIVES: To comprehensively identify and map an exhaustive list of value criteria for the assessment of next-generation sequencing/comprehensive genomic profiling (NGS/CGP), to be used as an aid in decision making. METHODS: We conducted a systematic review to identify existing value frameworks (VFs) applicable to any type of healthcare technology. VFs and criteria were mapped to a previously published Latin American (LA) VF to harmonize definitions and identify additional criteria and or subcriteria. Based on this analysis, we extracted a comprehensive, evidence-based list of criteria and subcriteria to be considered in the design of a NGS/CGP VF. RESULTS: A total of 42 additional VFs were compared with the LA VF, 88% were developed in high-income countries, 30% targeted genomic testing, and 16% specifically targeted oncology. A total of 242 criteria and subcriteria were extracted; 227 (94%) were fully/partially included in the LA VF; and 15 (6%) were new. Clinical benefit and economic aspects were the most common criteria. VFs oriented to genomic testing showed significant overlap with other VFs. Considering all criteria and subcriteria, a total of 18 criteria and 36 individual subcriteria were identified. CONCLUSIONS: Our study provides an evidence-based set of criteria and subcriteria for healthcare decision making useful for NGS/CGP as well as other health technologies. The resulting list can be beneficial to inform decision making and will serve as a foundation to co-create a multistakeholder NGS/CGP VF that is aligned with the needs and values of health systems and could help to improve patient access to high-value technologies.

Launch sequencing of pharmaceuticals with multiple therapeutic indications: evidence from seven countries.

BACKGROUND: New medicines are increasingly being identified as efficacious across multiple indications. The impact of current pricing and reimbursement policies on launch decisions across these indications remains unclear. OBJECTIVE: This paper, first, maps marketing authorisation and HTA coverage recommendation sequences of multi-indication medicines across Germany, France, England, Scotland, Canada, Australia, and the USA, and, second, evaluates the clinical characteristics, clinical development time and coverage recommendation time of multi-indication medicines, drawing comparisons between the first and subsequent indications of an approved molecule. METHODS: Medicine approvals by the Food and Drug Administration between 2009-2019 were screened to identify multi-indication products with approved oncology indications. Data on clinical trial characteristics, clinical performance and HTA outcomes were extracted from publicly available regulatory approval and HTA reports. RESULTS: Relative to subsequent indications, first indications were more likely to receive conditional marketing authorisation, have an orphan designation, have a single arm phase II pivotal trial and lower MCBS score. Subsequent indications had faster HTA coverage recommendation times in England and Canada. While the majority of first indications received HTA coverage recommendations across all settings, the proportion of subsequent indications with HTA coverage recommendations was lower and uptake varied considerably across settings. CONCLUSIONS: Discordance in the value of first versus subsequent indications can pose major challenges in systems that define price based on the initial indication. Current pricing and reimbursement systems generate significant fragmentation in the approval and availability of multi-indication products across settings.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA.

BACKGROUND: Previous research focused on the clinical evidence supporting new cancer drugs' initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. OBJECTIVES: To examine the clinical trial evidence supporting new targeted cancer drugs' initial and supplementary indication approval in the US, EU, Canada, and Australia. DATA AND METHODS: 25 cancer drugs across 100 indications were identified with FDA approval between 2009-2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07-6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38-8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17-5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14-30.65], p < 0.05) than supplementary indications. Initial indications' pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93-0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09-0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01-1.39], p < 0.05). CONCLUSIONS: Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication's differential clinical and economic value.

Hippocampal and parahippocampal volumes vary by sex and traumatic life events in children

Background: Childhood trauma is reliably associated with smaller hippocampal volume in adults; however, this finding has not been shown in children, and even less is known about how sex and trauma interact to affect limbic structural development in children. Methods: Typically developing children aged 9 to 15 years who completed a trauma history questionnaire and structural T1-weighted MRI were included in this study (n = 172; 85 female, 87 male). All children who reported 4 or more traumas (n = 36) composed the high trauma group, and all children who reported 3 or fewer traumas (n = 136) composed the low trauma group. Using multivariate analysis of covariance, we compared FreeSurfer-derived structural MRI volumes (normalized by total intracranial volume) of the amygdalar, hippocampal and parahippocampal regions by sex and trauma level, controlling for age and study site. Results: We found a significant sex × trauma interaction, such that girls with high trauma had greater volumes than boys with high trauma. Follow-up analyses indicated significantly increased volumes for girls and generally decreased volumes for boys, specifically in the hippocampal and parahippocampalregions for the high trauma group; we observed no sex differences in the low trauma group. We noted no interaction effect for the amygdalae. Limitations: We assessed a community sample and did not include a clinical sample. We did not collect data about the ages at which children experienced trauma. Conclusion: Results revealed that psychological trauma affects brain development differently in girls and boys. These findings need to be followed longitudinally to elucidate how structural differences progress and contribute to well-known sex disparities in psychopathology.

Attention bias variability and posttraumatic stress symptoms: the mediating role of emotion regulation difficulties.

Growing literature has linked attention bias variability (ABV) to the experience and treatment of posttraumatic stress disorder (PTSD). Unlike assessments of attention bias in only one direction, ABV captures dynamic fluctuations in attention toward and away from threat. While mechanisms underlying the ABV-PTSD relations are unclear, some research implicates emotion regulation difficulties. The current study examined in community women with varying PTSD symptom severity, the amount of variance in the association between ABV and PTSD accounted for by emotion regulation difficulties. The full sample (N = 74) was comprised of 59% community women with PTSD due to domestic and/or sexual violence, and 41% community women without PTSD. All participants completed self-report questionnaires including the Difficulties in Emotion Regulation Scale-16, which assessed emotion regulation. ABV was calculated following a computerised dot probe task. The indirect effect of ABV on PTSD symptom severity through emotion regulation difficulties was statistically significant, while the direct effect between ABV and PTSD symptom severity was not significant. Findings replicated after controlling for total trauma exposure. Clinical implications and literature suggesting how ABV may perpetuate emotion regulation difficulties associated with PTSD symptomology are discussed.

The developmental trajectory of sensorimotor cortical oscillations.

Numerous studies of motor control have confirmed beta and gamma oscillations in the primary motor cortices during basic movements. These responses include a robust beta decrease that precedes and extends through movement onset, a transient gamma response that coincides with the movement, and a post-movement beta rebound (PMBR) response that occurs after movement offset. While the existence of these responses has been confirmed by many studies, very few studies have examined their developmental trajectory. In the current study, we utilized magnetoencephalography (MEG) to investigate age-related changes in sensorimotor cortical oscillations in a large cross-section of children and adolescents (n = 94; age range = 9 -15 years-old). All participants performed a stimulus detection task with their right finger and the resulting MEG data were examined using oscillatory analysis methods and imaged using a beamformer. Consistent with adult studies, these youth participants exhibited characteristic beta (16-24 Hz) decreases prior to and during movement, as well as PMBR responses following movement offset, and a transient gamma (74-84 Hz) response during movement execution. Our primary findings were that the strength of the PMBR increased with age, while the strength of the gamma synchronization decreased with chronological age. In addition, the strength of each motor-related oscillatory response was significantly correlated with the power of spontaneous activity in the same frequency range and same voxel. This was the case for all three oscillatory responses. In conclusion, we investigated motor-related oscillatory activity in the largest cohort of children and adolescents reported to date, and our results indicated that beta and gamma cortical oscillations continue to develop as children transition into adolescents, and that these responses may not be fully matured until young to middle adulthood.

Neural dynamics of verbal working memory processing in children and adolescents.

Development of cognitive functions and the underlying neurophysiology is evident throughout childhood and adolescence, with higher order processes such as working memory (WM) being some of the last cognitive faculties to fully mature. Previous functional neuroimaging studies of the neurodevelopment of WM have largely focused on overall regional activity levels rather than the temporal dynamics of neural component recruitment. In this study, we used magnetoencephalography (MEG) to examine the neural dynamics of WM in a large cohort of children and adolescents who were performing a high-load, modified verbal Sternberg WM task. Consistent with previous studies in adults, our findings indicated left-lateralized activity throughout the task period, beginning in the occipital cortices and spreading anterior to include temporal and prefrontal cortices during later encoding and into maintenance. During maintenance, the occipital alpha increase that has been widely reported in adults was found to be relatively weak in this developmental sample, suggesting continuing development of this component of neural processing, which was supported by correlational analyses. Intriguingly, we also found sex-specific developmental effects in alpha responses in the right inferior frontal region during encoding and in parietal and occipital cortices during maintenance. These findings suggested a developmental divergence between males and females in the maturation of neural circuitry serving WM during the transition from childhood to adolescence.

tDCS modulates behavioral performance and the neural oscillatory dynamics serving visual selective attention.

Transcranial direct-current stimulation (tDCS) is a noninvasive method for modulating human brain activity. Although there are several hypotheses about the net effects of tDCS on brain function, the field's understanding remains incomplete and this is especially true for neural oscillatory activity during cognitive task performance. In this study, we examined whether different polarities of occipital tDCS differentially alter flanker task performance and the underlying neural dynamics. To this end, 48 healthy adults underwent 20 min of anodal, cathodal, or sham occipital tDCS, and then completed a visual flanker task during high-density magnetoencephalography (MEG). The resulting oscillatory responses were imaged in the time-frequency domain using beamforming, and the effects of tDCS on task-related oscillations and spontaneous neural activity were assessed. The results indicated that anodal tDCS of the occipital cortices inhibited flanker task performance as measured by reaction time, elevated spontaneous activity in the theta (4-7 Hz) and alpha (9-14 Hz) bands in prefrontal and occipital cortices, respectively, and reduced task-related theta oscillatory activity in prefrontal cortices during task performance. Cathodal tDCS of the occipital cortices did not significantly affect behavior or any of these neuronal parameters in any brain region. Lastly, the power of theta oscillations in the prefrontal cortices was inversely correlated with reaction time. In conclusion, anodal tDCS modulated task-related oscillations and spontaneous activity across multiple cortical areas, both near the electrode and in distant sites that were putatively connected to the targeted regions.

Aberrant occipital dynamics differentiate HIV-infected patients with and without cognitive impairment.

Combination antiretroviral therapies have revolutionized the treatment of HIV infection, and many patients now enjoy a lifespan equal to that of the general population. However, HIV-associated neurocognitive disorders (HAND) remain a major health concern, with between 30% and 70% of all HIV-infected patients developing cognitive impairments during their life time. One important feature of HAND is visuo-perceptual deficits, but the systems-level neural dynamics underlying these impairments are poorly understood. In the current study, we use magnetoencephalography and advanced time series analyses to examine these neural dynamics during a visuospatial processing task in a group of HIV-infected patients without HAND (n = 25), patients with HAND (n = 18), and a group of demographically-matched uninfected controls (n = 24). All participants completed a thorough neuropsychological assessment, and underwent magnetoencephalography and structural MRI protocols. In agreement with previous studies, patients with HAND performed significantly worse than HIV-infected patients without HAND and controls on the cognitive task, in terms of increased reaction time and decreased accuracy. Our magnetoencephalography results demonstrated that both spontaneous and neural oscillatory activity within the occipital cortices were affected by HIV infection, and that these patterns predicted behavioural performance (i.e. accuracy) on the task. Specifically, spontaneous neural activity in the alpha (8-16 Hz) and gamma (52-70 Hz) bands during the prestimulus baseline period, as well as oscillatory theta responses (4-8 Hz) during task performance were aberrant in HIV-infected patients, with both spontaneous alpha and oscillatory theta activity significantly predicting accuracy on the task and neuropsychological performance outside of the magnetoencephalography scanner. Importantly, these rhythmic patterns of population-level neural activity also distinguished patients by HAND status, such that spontaneous alpha activity in patients with HAND was elevated relative to HIV-infected patients without HAND and controls. In contrast, HIV-infected patients with and without HAND had increased spontaneous gamma compared to controls. Finally, there was a stepwise decrease in oscillatory theta activity as a function of disease severity, such that the response diminished from controls to patients without HAND to patients with HAND. Interestingly, the strength of the relationship between this theta response and accuracy also dissociated patient groups in a similar manner (controls > HIV with no HAND > HIV with HAND), indicating a reduced coupling between neurophysiology and behaviour in HIV-infected patients. This study provides the first neuroimaging evidence of a dissociation between HIV-infected patients with and without HAND, and these findings shed new light on the neural bases of cognitive impairment in HIV infection.

tDCS Modulates Visual Gamma Oscillations and Basal Alpha Activity in Occipital Cortices: Evidence from MEG.

Transcranial direct-current stimulation (tDCS) is now a widely used method for modulating the human brain, but the resulting physiological effects are not understood. Recent studies have combined magnetoencephalography (MEG) with simultaneous tDCS to evaluate online changes in occipital alpha and gamma oscillations, but no study to date has quantified the offline (i.e., after tDCS) alterations in these responses. Thirty-five healthy adults received active or sham anodal tDCS to the occipital cortices, and then completed a visual stimulation paradigm during MEG that is known to elicit robust gamma and alpha oscillations. The resulting MEG data were imaged and peak voxel time series were extracted to evaluate tDCS effects. We found that tDCS to the occipital increased the amplitude of local gamma oscillations, and basal alpha levels during the baseline. tDCS was also associated with network-level effects, including increased gamma oscillations in the prefrontal cortex, parietal, and other visual attention regions. Finally, although tDCS did not modulate peak gamma frequency, this variable was inversely correlated with gamma amplitude, which is consistent with a GABA-gamma link. In conclusion, tDCS alters gamma oscillations and basal alpha levels. The net offline effects on gamma activity are consistent with the view that anodal tDCS decreases local GABA.

HTA Barriers for Conditional Approval Drugs.

BACKGROUND: Conditional approval pathways facilitate accelerated marketing authorisation based on immature clinical evidence for drugs that address an unmet medical need in a life-threatening or chronically debilitating condition. Lowering evidence requirements for marketing authorisation results in higher clinical uncertainty, which may present challenges for the health technology assessment (HTA) of these products. OBJECTIVES: The objective of this study is to assess whether conditionally approved drugs face higher probabilities of HTA rejection or delays in HTA approval relative to drugs with standard marketing authorisation. METHODS: This paper adopts a mixed-methods approach to provide a meta-analysis of HTA outcomes across 80 drug-indication pairs in France, England, Scotland and Canada. Differences in the characteristics (i.e. disease rarity and clinical trial design) of conditionally approved drugs and drugs with standard marketing authorisation and drivers of HTA outcomes are assessed through logistics regressions. Delays in HTA approval are assessed through a survival analysis. RESULTS: Relative to standard approval drugs, conditionally approved drugs are less likely to include phase III trial designs, less likely to include clinical endpoints and less likely to include an active comparator. Uncertainties in clinical and economic evidence are raised more frequently by HTA agencies for conditionally approved drugs, which have a marginally lower probability of receiving HTA approval relative to drugs with standard approval. Conditionally approved drugs face moderate delays (an average of 6 months) in receiving HTA approval relative to standard approval drugs. CONCLUSIONS: Overall, conditionally approved drugs likely face increased barriers at the HTA level.

Healthcare Payer Perspectives on the Assessment and Pricing of Oncology Multi-Indication Products: Evidence from Nine OECD Countries.

BACKGROUND: New pharmaceuticals are increasingly being developed for use across multiple indications. Countries across Europe and North America have adopted a range of different approaches to capture differences in the value of individual indications. OBJECTIVE: The three aims of this study were (i) to review the price-setting practice over the past 5 years for multi-indication products across England, France, Italy, Spain, Belgium, Switzerland, Turkey, Canada and the USA; (ii) to assess the impact of current practices on launch strategy; and (iii) to identify issues in the implementation of indication-based pricing. METHODS: Ten current and former members of health insurance organisations, healthcare payer organisations or health technology assessment agencies with expertise on pharmaceutical purchasing were invited to participate in semi-structured interviews. Interview transcripts were imported into NVivo 12 for thematic analysis. RESULTS: The majority of countries studied require full assessments upon launch of a new indication. Five different approaches to pricing were identified: weighted pricing, differential discounting, mandatory discount, price anchoring and free pricing. Manufacturers show a tendency to launch first in niche indications with high unmet need to achieve a high price. Stakeholders from England, France, Italy, Belgium and Switzerland consider their current system fit for purpose, while other countries expressed concern over the administrative burden of monitoring products at indication level. CONCLUSIONS: Given the high administrative burden, it is questionable whether indication-based pricing would provide additional public benefit above and beyond current weighted dynamic single pricing and differential discounting practices for multi-indication products.

How do HTA agencies perceive conditional approval of medicines? Evidence from England, Scotland, France and Canada.

There is a growing disconnect between regulatory agencies that are promoting expedited approval to medicines based on early phase clinical evidence and health technology assessment (HTA) agencies that require robust clinical evidence to inform coverage decisions. This paper provides an assessment of the evidence gap between regulatory and HTA agencies on medicines receiving conditional marketing authorisation (CMA) and examines how HTA agencies in France, England, Scotland, and Canada interpret and appraise evidence for these medicines. A mixed methods research design was used to identify the types and frequency of parameters raised in the context of HTA decision-making for all conditional approvals in Europe and Canada between 2010 and 2017. Significant heterogeneity was found across the HTA agencies in England, Scotland, France, and Canada in the assessment of medicines receiving CMA, with the highest likelihood of rejection present in Quebec (50%) and Scotland (25%). Rejected medicines were more likely to have unresolved uncertainties related to the magnitude of clinical benefit, study design, and issues in economic modelling. More systematic use of joint early dialogue and conditional reimbursement pathways would help clarify evidence requirements and avoid delays in patient access to innovative medicines.

Value and Price of Multi-indication Cancer Drugs in the USA, Germany, France, England, Canada, Australia, and Scotland.

PURPOSE: Oncology drugs are often approved for multiple indications, for which their clinical benefit varies. Aligning a single price to this differing value remains a challenge. This study examines the clinical and economic value, price, and reimbursement of multi-indication cancer drugs across seven countries, representing different approaches to value assessment, pricing, and coverage decisions: the USA, Germany, France, England, Canada, Australia, and Scotland. METHODS: Twenty-five multi-indication cancer drugs across 100 indications were identified with US Food and Drug Administration (FDA) approval between 2009 and 2019. For each indication data on Health Technology Assessment (HTA) recommendations, disease prevalence, and drug prices were obtained. Quality-adjusted life years (QALYs) gained, disease prevalence, list prices, and HTA outcomes were then compared across indications and regions. RESULTS: First approved indications provide a higher clinical benefit whilst targeting a smaller patient group than indication extensions. Quality-adjusted life year gains were higher for first (0.99, 95% CI 0.05-3.25) compared to second (0.51, 95% CI 0.02-1.63, p < 0.001) and third (0.58, 95% CI 0.05-2.07, p < 0.01) approved indications. Disease prevalence per 100,000 inhabitants was 20.7 (95% CI 0.2-63.3) for first compared to 27.1 (95% CI 1.5-109.6, p = 0.907) for second and 128.3 (95% CI 3.1-720.1, p < 0.001) for third approved indications. With each approved indication drug prices declined in Germany and France, remained constant in the UK, Canada, and Australia, whilst they increased in the USA. Negative HTA outcomes, clinical restrictions, and managed entry agreements (MEAs) were more frequently observed for indication extensions. CONCLUSIONS: Results suggest that indication development is prioritised according to clinical value and disease prevalence. Countries employ different mechanisms to account for each indication's differential benefit, e.g., weighted-average prices (Germany, France, Australia), differential discounts (England, Scotland), clinical restrictions, and MEAs (England, Scotland, Australia, Canada). Value-based indication-specific pricing can help to align the benefit and price for multi-indication cancer drugs.

The future of oncology policy.

To ensure the previous progress seen in cancer survival rates continues as we move through the 21st Century it is important to determine future effective policy related to oncology healthcare delivery and funding. Recent successes with, for example, the COVID vaccine response, the decision-making agility exhibited by governments and healthcare systems and the effective use of telehealth and real-world evidence highlight the progress that can be made with pooled efforts and innovative thinking. This shared approach is the basis for the European Beating Cancer Plan which outlines action points for governments and health systems for the period 2021-2025. It focuses on a whole government approach, centred on patients, maximising the potential of new technologies and insights across policy areas including employment, education, transport and taxation, enabling the tackling of cancer drivers in schools, workplaces, research labs, towns and cities and rural communities. Despite the plan there are still concerns that oncology policy has not adequately responded to the pace of innovation and the unique challenges generated by innovative oncological technologies. There needs to be focus on: gaining consensus on the most appropriate methods to assess and price combination therapies and cell and gene therapies, developing effective outcome-based payment models for personalised medicine and developing consensus on the ideal approach for multiple indication pricing. Finally, future policy needs to ensure pharmaceutical companies and other research organisations are adequately rewarded for innovation to ensure continued R&D and the development of innovative oncological products.

Sin taxes and their effect on consumption, revenue generation and health improvement: a systematic literature review in Latin America.

Sin or public health taxes are excise taxes imposed on the consumption of potentially harmful goods for health [sugar-sweetened beverages (SSBs), tobacco, alcohol, among others], aiming to reduce consumption, raise additional revenue and/or improve population health. This paper assesses the extent to which sin taxes (a) can reduce consumption of potentially harmful goods, (b) raise revenue for national health systems and (c) contribute to population health in Latin America. A systematic literature review was conducted on peer-reviewed and grey literature; endpoints included: impact of raising sin taxes on consumption, ability to raise revenue for health and the possibility of population health improvements. Risk of bias for each study was assessed. The synthesis of the literature on sin tax implementation showed improvements in all three endpoints across the study countries. Following the introduction of sin taxes or by simulating their potential impact, nearly all studies explicitly reported that consumption of potentially harmful goods (mainly SSBs and tobacco) declined; revenue was found to have increased in almost all countries, suggesting that there may be additional scope for further tax increase. Simulated improvements in population health have also been shown, by demonstrating a relationship between sin tax increases and reduction in prevalence of diabetes, stroke, heart attacks and associated deaths. However, sin tax effects on health would be better quantified over the long-term. Data quality and availability challenges did place some limitations on sin tax impact assessment. Sin taxes can be effective in reducing consumption of potentially harmful goods, improve population health and generate additional revenue. Promoting further research on this topic should be a priority.

Examining the Factors that Contribute to Non-Monotonic Growth of the [Formula: see text] Otoacoustic Emission in Humans.

Cubic distortion product otoacoustic emission input-output functions in humans show a complex pattern of growth. To further investigate the growth of the [Formula: see text] otoacoustic emission, magnitude and phase input-output functions were obtained from human subjects using a range of stimulus levels, frequencies, and frequency ratios. Three factors related to cochlear nonlinearity may produce non-monotonic input-output functions: a two-component interaction, an operating point shift, and two-tone suppression. To complement data interpretation, a local model of distortion product otoacoustic emission generation was fit to the magnitude spectrum of the averaged ear canal sound pressure recording to quantify operating point shift. Results obtained are consistent with non-monotonic growth occurring primarily as a result of two-tone suppression and/or a two-component interaction. These two mechanisms are expected to operate at different stimulus levels, with different signature magnitude and phase patterns, and are unlikely to overlap in producing non-monotonic growth. An operating point shift was suggested in three cases. These results support multiple factors contributing to the complexity of growth of the [Formula: see text] otoacoustic emission in humans and highlight the importance of looking at phase in addition to magnitude when interpreting distortion product otoacoustic emission growth.

Do pharmaceutical budgets deliver financial sustainability in healthcare? Evidence from Europe.

Payers have increasingly implemented a variety cost-containment measures to promote sustainability in the pharmaceutical sector. This paper provides an assessment of a range of different applications of pharmaceutical budgets and assesses their impact in the context of health financing goals. A comprehensive literature review was carried out in order to identify evidence on the presence and impact of pharmaceutical budget-setting and capping mechanisms and an analytical framework was developed outlining relevant tradeoffs between macroeconomic and microeconomic efficiency. Evidence from the literature was validated by expert opinion through a round-table meeting followed by a series of semi-structured interviews. Five broad types of pharmaceutical budgets were identified as relevant : global, regional, disease-specific, product-specific, and prescribing. Fixed global budgets on total pharmaceutical expenditure are used primarily to promote cost-containment; however, their use often restricts flexibility in terms of total health budget allocation. Disease-specific budgets without consequences for exceeding the budget are unlikely to promote fiscal sustainability as these budgets are frequently exceeded. Product-specific budgets and prescribing budgets can play an important role in contributing to microeconomic efficiency; however, evidence on their impact is mixed. Overall, pharmaceutical budgets are present at both macroeconomic and microeconomic levels. While they are important tools for promoting fiscal sustainability, additional policy measures are needed to further enhance value for money in the pharmaceutical sector.

Traumatic Events Are Associated with Diverse Psychological Symptoms in Typically-Developing Children.

Childhood traumatic events are significant risk factors for psychopathology according to adult retrospective research; however, few studies examine trauma exposure and psychological symptoms in pre-adolescent children. Typically-developing children, aged 9-12 years (N = 114), were recruited from the community and selected from the Developmental Chronnecto-Genomics (Dev-CoG) study examining child development. Children completed questionnaires about traumatic life events, posttraumatic stress, anxiety, depression, dissociation, anger, and internalizing and externalizing behaviors. Parents also completed internalizing and externalizing measures. The number of traumatic events significantly correlated with symptom severity across all child-report psychological measures, but surprisingly, trauma was not correlated with any parent-report scores. Follow-up analyses revealed a significant trauma effect for internalizing and externalizing behaviors according to child self-report, but not for parent-report measures. Results indicate that childhood trauma may be a non-specific risk factor for sub-clinical psychopathology in otherwise typically-developing children. Moreover, children appear to be the most appropriate reporters of their own psychological distress.

Perception of noise-vocoded tone complexes: A time domain analysis based on an auditory filterbank model.

When a wideband harmonic tone complex (wHTC) is passed through a noise vocoder, the resulting sounds can have spectra with large peak-to-valley ratios, but little or no periodicity strength in the autocorrelation functions. We measured judgments of pitch strength for normal-hearing listeners for noise-vocoded wideband harmonic tone complexes (NV-wHTCs) relative to standard and anchor stimuli. The standard was a 1-channel NV-wHTC and the anchor was either the unprocessed wHTC or an infinitely-iterated rippled noise (IIRN). Although there is variability among individuals, the magnitude judgment functions obtained with the IIRN anchor suggest different listening strategies among individuals. In order to gain some insight into possible listening strategies, test stimuli were analyzed at the output of an auditory filterbank model based on gammatone filters. The weak periodicity strengths of NV-wHTCs observed in the stimulus autocorrelation functions are augmented at the output of the gammatone filterbank model. Six analytical models of pitch strength were evaluated based on summary correlograms obtained from the gammatone tone filterbank. The results of the filterbank analysis suggest that, contrary to the weak or absent periodicity strengths in the stimulus domain, temporal cues contribute to pitch strength perception of noise-vocoded harmonic stimuli such that listeners' judgments of pitch strength reflect a nonlinear, weighted average of the temporal information between the fine structure and the envelope.