Transcranial Direct Current Stimulation Combined With Listening to Preferred Music Alters Cortical Speech Processing in Older Adults

Emerging evidence suggests transcranial direct current stimulation (tDCS) can improve cognitive performance in older adults. Similarly, music listening may improve arousal and stimulate subsequent performance on memory-related tasks. We examined the synergistic effects of tDCS paired with music listening on auditory neurobehavioral measures to investigate causal evidence of short-term plasticity in speech processing among older adults. In a randomized sham-controlled crossover study, we measured how combined anodal tDCS over dorsolateral prefrontal cortex (DLPFC) paired with listening to autobiographically salient music alters neural speech processing in older adults compared to either music listening (sham stimulation) or tDCS alone. EEG assays included both frequency-following responses (FFRs) and auditory event-related potentials (ERPs) to trace neuromodulation-related changes at brainstem and cortical levels. Relative to music without tDCS (sham), we found tDCS alone (without music) modulates the early cortical neural encoding of speech in the time frame of ∼100–150 ms. Whereas tDCS by itself appeared to largely produce suppressive effects (i.e., reducing ERP amplitude), concurrent music with tDCS restored responses to those of the music+sham levels. However, the interpretation of this effect is somewhat ambiguous as this neural modulation could be attributable to a true effect of tDCS or presence/absence music. Still, the combined benefit of tDCS+music (above tDCS alone) was correlated with listeners’ education level suggesting the benefit of neurostimulation paired with music might depend on listener demographics. tDCS changes in speech-FFRs were not observed with DLPFC stimulation. Improvements in working memory pre to post session were also associated with better speech-in-noise listening skills. Our findings provide new causal evidence that combined tDCS+music relative to tDCS-alone (i) modulates the early (100–150 ms) cortical encoding of speech and (ii) improves working memory, a cognitive skill which may indirectly bolster noise-degraded speech perception in older listeners

Educating a culturally competent health workforce for Pasifika communities: A Wintec/K'aute Pasifika clinical partnership project

Introduction The connection between Wintec and K’aute Pasifika is long standing through health and education and the time is right for collaboration that lifts both organisations is the strongest possible partnership. Significant opportunity exists for Wintec’s CHASP/CSSHP and K’aute Pasifika to work together in developing innovative strategies to enhance opportunities for student engagement in the delivery of services offered through K’aute Pasifika and to evaluate these. Literature review Pacific Islanders typically have lower health status and life expectancy than other New Zealanders. Implementation of Māori initiatives are not always appropriate for Pasifika peoples and there is a need to develop Pacific-specific initiatives. Evidence suggests tailored teaching and learning interventions may be required to promote participation and academic success of underrepresented minority groups in New Zealand, such as Pasifika. However, the focus needs to be on more than just Pasifika students and also on increasing non-Pasifika student capacity to work with the Pasifika community in a culturally acceptable and competent manner. There is a consistent shortage of Pacific primary health care workers in New Zealand and Pasifika are underrepresented across all health occupations. The literature identifies a complex range of factors that may contribute to this including high levels of mobilization in the skilled professional workforce and blurring of boundaries. Student-led placements with Indigenous populations have been identified as a feasible and meaningful way of developing a workforce ready to serve Indigenous and minority populations. Method A mixed method study design incorporating Talanoa was implemented to address the following key objectives: 1. Map current Wintec student placement provision within K’aute Pasifika against regional population health needs 2. Identify educational opportunities available at K’aute Pasifika through consultation with K’aute Pasifika staff 3. In collaboration between Wintec and K’aute Pasifika, develop a 5-year strategic plan for enhancement of cultural competence of Wintec staff and students in working with Pasifika people Findings Our Talanoa identified three major themes through which current and potential student placements could be better understood: the student experience, vā/relationships, and transformation. The first theme, student experience, was divided into subthemes, which expressed how students are valued, quality experiences for students are important to K’aute Pasifika staff, cultural practices are significant in placements at K’aute Pasifika, authentic experiences and interprofessional practices are essential and readily occur at K’aute Pasifika. The second theme, vā/relationships, was conceptualised as a network, with K’aute Pasifika at the centre, surrounded by the relevant partnerships. Equally as important as who those partners were, was the connections and space - or vā - between them. The third theme, transformation, was divided into three sub-themes: growth, capacity for more, and workforce development. These themes were understood in the context of the health data to create a clearer picture of the health needs for the Pasifika community in Kirikiriroa/Hamilton. Recommendations A clear action plan for 2021 is outlined which was co-constructed and agreed between K’aute Pasifika and Wintec and derived from the Strategic Plan

Age dating of an early Milky Way merger via asteroseismology of the naked-eye star ν Indi

Over the course of its history, the Milky Way has ingested multiple smaller satellite galaxies1. Although these accreted stellar populations can be forensically identified as kinematically distinct structures within the Galaxy, it is difficult in general to date precisely the age at which any one merger occurred. Recent results have revealed a population of stars that were accreted via the collision of a dwarf galaxy, called Gaia–Enceladus1, leading to substantial pollution of the chemical and dynamical properties of the Milky Way. Here we identify the very bright, naked-eye star ν Indi as an indicator of the age of the early in situ population of the Galaxy. We combine asteroseismic, spectroscopic, astrometric and kinematic observations to show that this metal-poor, alpha-element-rich star was an indigenous member of the halo, and we measure its age to be 11.0±0.7 (stat) ±0.8 (sys) billion years. The star bears hallmarks consistent with having been kinematically heated by the Gaia–Enceladus collision. Its age implies that the earliest the merger could have begun was 11.6 and 13.2 billion years ago, at 68% and 95% confidence, respectively. Computations based on hierarchical cosmological models slightly reduce the above limits

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. FUNDING: Bill & Melinda Gates Foundation

Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016

The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an