Salience Network Segregation Mediates the Effect of Tau Pathology on Mild Behavioral Impairment.

INTRODUCTION: A recently developed mild behavioral impairment (MBI) diagnostic framework standardizes the early characterization of neuropsychiatric symptoms in older adults. However, the links between MBI, brain function, and Alzheimer's disease (AD) biomarkers are unclear. METHODS: Using data from 128 participants with diagnosis of amnestic mild cognitive impairment and mild dementia - Alzheimer's type, we test a novel model assessing direct relationships between AD biomarker status and MBI symptoms, as well as mediated effects through segregation of the salience and default-mode networks. RESULTS: We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other high-level, association networks. There were no direct effects of AD biomarkers status on MBI. DISCUSSION: Our findings suggest an indirect role of tau pathology in MBI through brain network dysfunction and emphasize the role of the salience network in mediating relationships between neuropathological changes and behavioral manifestations.

Five-Year Trends of Vascular Disease-Related Amputations in Romania: A Retrospective Database Study.

Background/Objectives: Lower extremity amputations (LEAs) are a burdensome complication of peripheral artery disease (PAD) and/or arterial embolism and thrombosis (AET). We assessed the trends in PAD- and/or AET-related LEAs in Romania. Methods: This retrospective study (2015-2019) analyzed data on minor and major LEAs in hospitalized patients recorded in the National School for Public Health, Management, and Health Education database. The absolute numbers and incidences of LEAs were analyzed by diagnosis type, year, age, sex, and amputation level. Results: Of 38,590 vascular disease-related amputations recorded nationwide, 36,162 were in PAD and 2428 in AET patients. The average LEA incidence in the general population was 34.73 (minimum: 31.96 in 2015; maximum: 36.57 in 2019). The average incidence of major amputations, amputations above the knee, hip amputations, amputations below the knee, and minor amputations was 16.21 (15.62 in 2015; 16.84 in 2018), 13.76 (13.33 in 2015; 14.28 in 2018), 0.29 (0.22 in 2017; 0.35 in 2019), 2.15 (2.00 in 2015; 2.28 in 2019), and 18.52 (16.34 in 2015; 20.12 in 2019), respectively. Yearly PAD- and/or AET-related amputations were significantly higher in men versus women. The overall number of LEAs increased with age, particularly in patients ≥ 70 years. The increase in the total number of amputations was mainly due to a constant rise in minor amputations for both groups, regardless of gender. Conclusions: PAD- and/or AET-related LEAs in Romania increased from 2015 to 2019, with men having a greater incidence than women. Raising awareness and effective management strategies are needed to prevent LEAs.

Political Determinants of Health: Healthcare Privatization and Population Health in Europe.

The extent to which healthcare reforms affect health remains understudied. Healthcare reforms result in policy outputs that determine provision of medical services, which have consequences for the health of the population. We scrutinize this relationship between health policy outputs and population health, using an original dataset of healthcare reforms passed in 36 European countries from 1989 to 2019. Focusing more specifically on legislative changes implying privatization of healthcare delivery and finance, we ask the following question: What is the relationship between reforms that privatize healthcare provision and population health in terms of health outcomes and inequalities? We answer this question by relying on fixed effects time-series cross-section models. Health outcomes are operationalized using measures of subjective health status, unmet health needs and resulting health inequalities. Our results show that privatization of healthcare is associated with higher rates of bad subjective health and unmet health needs several years after the passing of reforms. These effects are stronger for individuals in the lower tiers of income and education, resulting in higher socio-economic inequalities. The article contributes to conceptualization of the political determinants of health as health policy outputs and a better understanding of the relationship between policy outputs and population health outcomes.

Comparing high definition transcranial direct current stimulation to left temporoparietal junction and left inferior frontal gyrus for logopenic primary progressive aphasia: A single-case study.

Logopenic variant primary progressive aphasia (lvPPA) is characterized by word-finding deficits and phonologic errors in fluent speech. Transcranial direct current stimulation (tDCS) targeting either left temporoparietal junction (TPJ) or left inferior frontal gyrus (IFG) show evidence of improving language function in lvPPA. The present case study evaluated the effects of two separate rounds of high definition tDCS (HD-tDCS) (4 mA; 30 sessions) on language and functional neuroimaging in a 57-year-old woman with lvPPA. Stimulation was centred on two different regions across rounds: (1) left TPJ, and (2) left (IFG). Results showed an improved proportion of content to floorholder words during a naturalistic speech task through both rounds as well as change in confrontation naming after TPJ (improvement) and IFG (worsened) stimulation. fMRI connectivity during task showed left lateralized positive correlations following round 1 and anti-correlations with components of the default mode network following round 2. Resting state segregation of a language-associated functional network increased following both rounds, and task-based segregation of the same network increased following IFG stimulation. These results suggest that stimulation to both regions using HD-tDCS may improve language function in lvPPA, while simultaneously eliciting widespread changes beyond the targeted area in neuronal activity and functional connectivity.

Biden or Trump? Working memory for emotion predicts the ability to forecast future feelings.

Affective forecasting-the ability to predict how different outcomes will make us feel-is a crucial aspect of making optimal decisions. Recent laboratory evidence suggests that working memory for emotion is a basic psychological mechanism underlying forecasting ability: Individual differences in affective working memory predict how accurately people can forecast their future feelings whereas measures of "cognitive" working memory do not. Here, we demonstrate that this selective relationship between affective forecasting and affective working memory generalizes to forecasted feelings about a major real-world event. We report results from a preregistered (online) study (N = 76) demonstrating that affective working memory performance predicted how accurately people anticipate their feelings about the outcome of the 2020 U.S. presidential election. This relationship was specific to affective working memory and was also demonstrated in a description-based forecasting measure with emotionally evocative photographs, replicating previous results. However, neither affective nor cognitive working memory was related to a novel event-based forecasting questionnaire, adapted to compare predicted and experienced feelings to everyday events. Together, these findings advance a mechanistic understanding of affective forecasting and underscore the potential importance of affective working memory in some forms of higher order emotional thought. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Tolerability and blinding of high-definition transcranial direct current stimulation among older adults at intensities of up to 4 mA per electrode.

BACKGROUND: Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA). OBJECTIVE: We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members. METHODS: Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency. RESULTS: There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no ("none") or "mild" sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (<2 mA) than higher (≥3 mA) amplitude active sessions, while skin redness was significantly more common after higher amplitudes. Blinding was effective at the participant and study team levels. CONCLUSIONS: HD-tDCS was well tolerated with center electrode amplitudes up to 4 mA. The bimodal ramp-up/down format of the sham was effective for blinding. These results support higher scalp-based amplitudes that enable greater brain-based current intensities in older adults.

ConnSearch: A framework for functional connectivity analysis designed for interpretability and effectiveness at limited sample sizes.

Functional connectivity studies increasingly turn to machine learning methods, which typically involve fitting a connectome-wide classifier, then conducting post hoc interpretation analyses to identify the neural correlates that best predict a dependent variable. However, this traditional analytic paradigm suffers from two main limitations. First, even if classifiers are perfectly accurate, interpretation analyses may not identify all the patterns expressed by a dependent variable. Second, even if classifiers are generalizable, the patterns implicated via interpretation analyses may not replicate. In other words, this traditional approach can yield effective classifiers while falling short of most neuroscientists' goals: pinpointing the neural correlates of dependent variables. We propose a new framework for multivariate analysis, ConnSearch, which involves dividing the connectome into components (e.g., groups of highly connected regions) and fitting an independent model for each component (e.g., a support vector machine or a correlation-based model). Conclusions about the link between a dependent variable and the brain are based on which components yield predictive models rather than on interpretation analysis. We used working memory data from the Human Connectome Project (N = 50-250) to compare ConnSearch with four existing connectome-wide classification/interpretation methods. For each approach, the models attempted to classify examples as being from the high-load or low-load conditions (binary labels). Relative to traditional methods, ConnSearch identified neural correlates that were more comprehensive, had greater consistency with the WM literature, and better replicated across datasets. Hence, ConnSearch is well-positioned to be an effective tool for functional connectivity research.

A unified autonomous Europe? Public opinion of the EU's foreign and security policy.

The Russian invasion of Ukraine has pushed the EU into a new phase where both the political elites and the public start to rethink its foreign and security policies. This paper uses a unique survey in seven European countries in the wake of the war to examine European public opinion on how the EU's foreign and security policies should be made and how autonomous they should be. We find that Europeans not only favour increasing military capacity at the national or NATO level but also prefer increasing military capacity at the EU level, though to a lesser degree. We also show that perceptions of both short-term and long-term threats, European identification and mainstream left-wing ideology lead Europeans to favour a more militarily powerful, unified and autonomous EU.

The Mutational Landscape of Cancer's Vulnerability to Ionizing Radiation.

PURPOSE: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown. EXPERIMENTAL DESIGN: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized on the basis of genotype-phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts. RESULTS: We show that resistance to radiation is characterized by substantial inter- and intra-gene allelic variation. Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. We combined results from our platform with gene expression and metabolite features and identified the upregulation of amino acid transporters that facilitate oxidative reductive capacity and cell-cycle deregulation as key regulators of radiation sensitivity. CONCLUSIONS: Our results reveal new insights into the genetic determinants of tumor sensitivity to radiotherapy and nominate a multitude of cancer mutations that are predicted to impact treatment efficacy.

Toward rational use of cognitive training in those with mild cognitive impairment.

The term cognitive training includes a range of techniques that hold potential for treating cognitive impairment caused by neurologic injury and disease. Our central premise is that these techniques differ in their mechanisms of action and therefore engage distinct brain regions (or neural networks). We support this premise using data from a single-blind randomized-controlled trial in which patients with mild cognitive impairment were randomized to either mnemonic strategy training (MST) or spaced retrieval training (SRT) as they learned ecologically relevant object-location associations. Both training approaches were highly effective in the short term, but MST demonstrated a clear advantage after days to weeks. MST also increased activation in and functional connectivity between frontal, temporal, and parietal regions as well as the hippocampus. In contrast, patterns of reduced activation and functional connectivity were evident following SRT. These findings support the rational development of cognitive training techniques.

MENUS-Materials engineering by neutron scattering.

Materials engineering by neutron scattering (MENUS) at the second target station will be a transformational high-flux, versatile, multiscale materials engineering diffraction beamline with unprecedented new capabilities for the study of complex materials and structures. It will support both fundamental and applied materials research in a broad range of fields. MENUS will combine unprecedented long-wavelength neutron flux and unique detector coverage to enable real-time studies of complex structural and functional materials under external stimuli. The incorporated small angle neutron scattering and transmission/imaging capabilities will extend its sensitivity to larger length scales and higher spatial resolution. Multimodal MENUS will provide crystallographic and microstructure data to the materials science and engineering community to understand lattice strain/phase transition/microstructure/texture evolution in three orthogonal directions in complex material systems under combined extreme applied conditions. The capabilities of MENUS will open new scientific opportunities and meet the research needs for science challenges to enable studies of a range of phenomena and answer the key questions in material design/exploration, advanced material processing, transformative manufacturing, and material operations of national impacts in our daily life.

Occurrence of Potentially Toxic Elements in Bottled Drinking Water-Carcinogenic and Non-Carcinogenic Risks Assessment in Adults via Ingestion.

The presence of potentially toxic elements in drinking water can be dangerous for human health because of their bioaccumulation and toxicity, which is a huge concern for many researchers. In the case of bottled water, the exposure to toxic elements is achieved, especially by ingestion, leading to disorders of important functions of the human body. The aim of this study was the detection of some potentially toxic elements, from 50 samples of bottled drinking water, available on the Romanian market. Based on obtained concentrations, an assessment of the carcinogenic and non-carcinogenic health risk was performed. The concentrations of potentially toxic elements analyzed were below the maximum allowable limits, for all contaminants, excluding Pb and Fe. Moreover, the results of total risk via ingestion, showed that 30% of samples had an Hazard Quotient (HQ) < 1, and 70% had an HQ > 1; which implies a potential risk following the consumption of those samples. Concerning total cancer risk, 28% of the samples are in the acceptable level, while 72% of the samples are considered harmful and can lead to a type of cancer after repeated exposure. The study concluded that long term use of bottled water of poor quality may pose a hazard to human health; it is helpful for inhabitants to avoid ingestion of contaminated water.

High-definition transcranial direct current stimulation enhances network segregation during spatial navigation in mild cognitive impairment.

Spatial navigation is essential for everyday life and relies on complex network-level interactions. Recent evidence suggests that transcranial direct current stimulation (tDCS) can influence the activity of large-scale functional brain networks. We characterized brain-wide changes in functional network segregation (i.e. the balance of within vs. between-network connectivity strength) induced by high-definition (HD) tDCS in older adults with mild cognitive impairment (MCI) during virtual spatial navigation. Twenty patients with MCI and 22 cognitively intact older adults (healthy controls-HC) underwent functional magnetic resonance imaging following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right parietal cortex (center anode at P2) and delivered 2 mA for 20 min. Compared to HC, MCI patients showed lower brain-wide network segregation following sham HD-tDCS. However, following active HD-tDCS, MCI patients' network segregation increased to levels similar to those in HC, suggesting functional normalization. Follow-up analyses indicated that the increase in network segregation for MCI patients was driven by HD-tDCS effects on the "high-level"/association brain networks, in particular the dorsal-attention and default-mode networks. HD-tDCS over the right parietal cortex may normalize the segregation/integration balance of association networks during spatial navigation in MCI patients, highlighting its potential to restore brain activity in Alzheimer's disease.

The impact of focused attention on emotional evaluation: An eye-tracking investigation.

Emotional well-being depends on the ability to successfully engage a variety of coping strategies to regulate affective responses. Most studies have investigated the effectiveness of emotion regulation (ER) strategies that are deployed relatively later in the timing of processing that leads to full emotional experiences (i.e. reappraisal and suppression). Strategies engaged in earlier stages of emotion processing, such as those involved in attentional deployment, have also been investigated, but relatively less is known about their mechanisms. Here, we investigate the effectiveness of self-guided focused attention (FA) in reducing the impact of unpleasant pictures on the experienced negative affect. Participants viewed a series of composite images with distinguishable foreground (FG, either negative or neutral) and background (BG, always neutral) areas and were asked to focus on the FG or BG content. Eye-tracking data were recorded while performing the FA task, along with participants' ratings of their experienced emotional response following the presentation of each image. First, proving the effectiveness of self-guided FA in down-regulating negative affect, focusing away from the emotional content of pictures (BG focus) was associated with lower emotional ratings. Second, trial-based eye-tracking data corroborated these results, showing that spending less time gazing within the negative FG predicted reductions in emotional ratings. Third, this reduction was largest among subjects who habitually use suppression to regulate their emotions. Overall, the present findings expand the evidence regarding the FA's effectiveness in controlling the impact of emotional stimuli and inform the development of training interventions emphasizing attentional control to improve emotional well-being. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

An In Vitro Pull-down Assay of the E3 Ligase:PROTAC:Substrate Ternary Complex to Identify Effective PROTACs.

Assessing the specificity of PROTACs and confirming their proposed mechanism of action are critical for a robust targeted protein degradation program. Owing to their novel mechanism, new assays are needed to meet these goals. We and others have shown that a common explanation of PROTAC efficacy is the ability of the PROTAC to form a ternary complex between the E3 ubiquitin ligase and the target protein. In this chapter, we provide a simple in vitro method to quickly and inexpensively assess this property of PROTAC molecules. We provide detailed instructions for the purification of the specific E3 ubiquitin ligase VHL and then a generic protocol which can be adapted to any E3 ligase and substrate protein combination. This accessible method to study the ternary complex can strengthen any PROTAC-focused medicinal chemistry effort.

Proof-of-concept evidence for trimodal simultaneous investigation of human brain function.

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof-of-concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event-related potentials (ERPs), and event-related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.

Kinetic degradation and biocompatibility evaluation of polycaprolactone-based biologics delivery matrices for regenerative engineering of the rotator cuff.

Whereas synthetic biodegradable polymers have been successfully applied for the delivery of biologics in other tissues, the anatomical complexity, poor blood supply, and reduced clearance of degradation byproducts in the rotator cuff create unique design challenges for implantable biomaterials. Here, we investigated lower molecular weight poly-lactic acid co-epsilon-caprolactone (PLA-CL) formulations with varying molecular weight and film casting concentrations as potential matrices for the therapeutic delivery of biologics in the rotator cuff. Matrices were fabricated with target footprint dimensions to facilitate controlled and protected release of model biologic (Bovine Serum Albumin), and anatomically-unhindered implantation under the acromion in a rodent model of acute rotator cuff repair. The matrix obtained from the highest polymeric-film casting concentration showed a controlled release of model biologics payload. The tested matrices rapidly degraded during the initial 4 weeks due to preferential hydrolysis of the lactide-rich regions within the polymer, and subsequently maintained a stable molecular weight due to the emergence of highly-crystalline caprolactone-rich regions. pH evaluation in the interior of the matrix showed minimal change signifying lesser accumulation of acidic degradation byproducts than seen in other bulk-degrading polymers, and maintenance of conformational stability of the model biologic payload. The context-dependent biocompatibility evaluation in a rodent model of acute rotator cuff repair showed matrix remodeling without eliciting excessive inflammatory reaction and is anticipated to completely degrade within 6 months. The engineered PLA-CL matrices offer unique advantages in controlled and protected biologic delivery, non-toxic biodegradation, and biocompatibility overcoming several limitations of commonly-used biodegradable polyesters.

Age differences in functional network reconfiguration with working memory training.

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.

Affective forecasting: A selective relationship with working memory for emotion.

Affective forecasting (AF), the ability to predict one's future feelings, is important for decision making. We posit that AF entails the ability to maintain and evaluate an emotional feeling state, and thus requires affective working memory (AWM; Mikels & Reuter-Lorenz, 2019). To test this hypothesis, a series of studies investigated whether individual differences in AWM are related to AF ability. In the first study, we document that measures of AWM and AF are positively related, whereas an analogous measure of visual working memory is unrelated to AF in separate groups of participants. Two further within-group studies (1 preregistered) demonstrate that maintenance of affective information predicts AF performance, whereas maintenance of brightness information does not. Further, 2 additional measures of visual working memory (Corsi block-tapping and change detection) did not independently predict AF ability. Taken together the results demonstrate a reliable and selective relationship between AWM and AF, suggesting that AWM is a separable working memory subsystem and an elemental capacity that contributes to the type of higher-order emotional processes involved in AF. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Researching the Welfare Impact of Populist Radical Right Parties Comment on "A Scoping Review of Populist Radical Right Parties' Influence on Welfare Policy and its Implications for Population Health in Europe".

Populist radical right (PRR) parties can impact population health through multiple mechanisms, including welfare chauvinistic policies, influencing mainstream parties, and eroding democratic norms. Rinaldi and Bekker survey the literature in order to motivate a wider research agenda. They highlight results from existing studies which show the importance of looking into the impact of PRR parties on welfare policy. This commentary considers some of the areas of research highlighted by the original article, as well as other possibilities for further research. The most important of these is to expand the sample of cases to Central and Eastern Europe, Latin America, and South East Asia.