Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria.

OBJECTIVE: Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin ß-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities. DESIGN: To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation. RESULTS: BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits. CONCLUSION: Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with 'gut-first' PD.

Irisin enhances longevity by boosting SIRT1, AMPK, autophagy and telomerase.

Ageing is characterised by the accumulation of molecular and cellular damage through time, leading to a decline in physical and mental abilities. Currently, society has experienced a rapid increase in life expectancy, which has led to an increase in age-associated diseases. Therefore, it is crucial to study the process of ageing to guarantee the best conditions in the final stages of life. In recent years, interest has increased in a myokine known as irisin, which is secreted during physical exercise. This polypeptide hormone is produced by various organs, mainly muscle, and once it is released into the blood, it performs a wide variety of functions that are involved in metabolic control and may be relevant during some of the diseases associated with ageing. The aim of this review is to highlight the recent studies of irisin, such as its mechanism of expression, blood release, distribution, tissue target and participation in various cellular metabolic reactions and the relationship with key anti-ageing pathways such as adenosine monophosphate-activated protein kinase, silent information regulator T 1, autophagy and telomerase. In conclusion, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways. However, more research will be necessary to use this promising hormone for this gain.

Perceiving numerosity does not cause automatic shifts of spatial attention.

It is debated whether the representation of numbers is endowed with a directional-spatial component so that perceiving small-magnitude numbers triggers leftward shifts of attention and perceiving large-magnitude numbers rightward shifts. Contrary to initial findings, recent investigations have demonstrated that centrally presented small-magnitude and large-magnitude Arabic numbers do not cause leftward and rightward shifts of attention, respectively. Here we verified whether perceiving small or large non-symbolic numerosities (i.e., clouds of dots) drives attention to the left or the right side of space, respectively. In experiment 1, participants were presented with central small (1, 2) vs large-numerosity (8, 9) clouds of dots followed by an imperative target in the left or right side of space. In experiment 2, a central cloud of dots (i.e., five dots) was followed by the simultaneous presentation of two identical dot-clouds, one on the left and one on the right side of space. Lateral clouds were both lower (1, 2) or higher in numerosity (8, 9) than the central cloud. After a variable delay, one of the two lateral clouds turned red and participants had to signal the colour change through a unimanual response. We found that (a) in Experiment 1, the small vs large numerosity of the central cloud of dots did not speed up the detection of left vs right targets, respectively, (b) in Experiment 2, the detection of colour change was not faster in the left side of space when lateral clouds were smaller in numerosity than the central reference and in the right side when clouds were larger in numerosity. These findings show that perceiving non-symbolic numerosity does not cause automatic shifts of spatial attention and suggests no inherent association between the representation of numerosity and that of directional space.

The Hemispheric Distribution of α-Band EEG Activity During Orienting of Attention in Patients with Reduced Awareness of the Left Side of Space (Spatial Neglect).

EEG studies in healthy humans have highlighted that alpha-band activity is relatively reduced over the occipital-parietal areas of the hemisphere contralateral to the direction of spatial attention. Here, we investigated the hemispheric distribution of alpha during orienting of attention in male and female right brain-damaged patients with left spatial neglect. Temporal spectral evolution showed that in patients with neglect alpha oscillations over the damaged hemisphere were pathologically enhanced both during the baseline-fixation period that preceded cued orienting (capturing tonic alpha changes) and during orienting with leftward, rightward, or neutral-bilateral spatial cues (reflecting phasic alpha changes). Patients without neglect showed a similar though significantly less enhanced hemispheric asymmetry. Healthy control subjects displayed a conventional decrease of alpha activity over the hemisphere contralateral to the direction of orienting. In right-brain-damaged patients, neglect severity in the line bisection task was significantly correlated both with tonic alpha asymmetry during the baseline period and with phasic asymmetries during orienting of attention with neutral-bilateral and leftward cues. Asymmetries with neutral-bilateral and leftward cues were correlated with lesion of white matter tracts linking frontal with parietal-occipital areas. These findings show that disruption of rostrocaudal white matter connectivity in the right hemisphere interferes with the maintenance of optimal baseline tonic levels of alpha and the phasic modulation of alpha activity during shifts of attention. The hemispheric distribution of alpha activity can be used as a diagnostic tool for acquired pathological biases of spatial attention due to unilateral brain damage.SIGNIFICANCE STATEMENT Alpha desynchronization over the hemisphere contralateral to the attended side of space is a reliable marker of attentional orienting in the healthy human brain: can the same marker be used to spot and quantify acquired disturbances of spatial attention after unilateral brain injuries? Are pathological modifications in the hemispheric distribution of alpha specifically linked to attentional neglect for one side of space? We show that in patients with right brain damage the pathological enhancement of alpha oscillations over the parietal and occipital areas of the injured hemisphere is correlated with reduced awareness for the left side of space and with the lesion of white matter pathways that subserve frontal modulation of alpha activity in posterior brain areas.

Deconstructing Reorienting of Attention: Cue Predictiveness Modulates the Inhibition of the No-target Side and the Hemispheric Distribution of the P1 Response to Invalid Targets.

Orienting of attention produces a "sensory gain" in the processing of visual targets at attended locations and an increase in the amplitude of target-related P1 and N1 ERPs. P1 marks gain reduction at unattended locations; N1 marks gain enhancement at attended ones. Lateral targets that are preceded by valid cues also evoke a larger P1 over the hemisphere contralateral to the no-target side, which reflects inhibition of this side of space [Slagter, H. A., Prinssen, S., Reteig, L. C., & Mazaheri, A. Facilitation and inhibition in attention: Functional dissociation of pre-stimulus alpha activity, P1, and N1 components. Neuroimage, 125, 25-35, 2016]. To clarify the relationships among cue predictiveness, sensory gain, and the inhibitory P1 response, we compared cue- and target-related ERPs among valid, neutral, and invalid trials with predictive (80% valid/20% invalid) or nonpredictive (50% valid/50% invalid) directional cues. Preparatory facilitation over the visual cortex contralateral to the cued side of space (lateral directing attention positivity component) was reduced during nonpredictive cueing. With predictive cues, the target-related inhibitory P1 was larger over the hemisphere contralateral to the no-target side not only in response to valid but also in response to neutral and invalid targets: This result highlights a default inhibitory hemispheric asymmetry that is independent from cued orienting of attention. With nonpredictive cues, valid targets reduced the amplitude of the inhibitory P1 over the hemisphere contralateral to the no-target side whereas invalid targets enhanced the amplitude of the same inhibitory component. Enhanced inhibition was matched with speeded reorienting to invalid targets and drop in attentional costs. These findings show that reorienting of attention is modulated by the combination of cue-related facilitatory and target-related inhibitory activity.

Spatial uncertainty improves the distribution of visual attention and the availability of sensory information for conscious report.

Picking-up and exploiting spatial and temporal regularities in the occurrence of sensory events is important for goal-directed behaviour. According to the "Predictive Coding Hypothesis" (Friston Philosophical Trans R Soc B 360(1456):815-836, 2005), these regularities are used to generate top-down predictions that are constantly compared with actual sensory events. In a previous study with the Attentional Blink (AB) paradigm, we showed that the temporal and probabilistic uncertainty of T2s that are presented outside the Attentional Blink period, i.e. at least 400 ms after T1, improves the conscious report of T2 that are presented inside the AB. The study of ERP correlated showed that this improvement was associated with a prolonged storage of pre-conscious T2 traces in extra-striate areas (Lasaponara et al. Cortex 71:15-33, 2015). Here, we tested whether variations in the probabilistic cueing of the position of a primary T1 visual target in a 4 × 4 letter array, modulate the retention of memory traces evoked by secondary letter targets (T2) that were presented in other positions of the array. Most important, in each trial, the identity of T2 was specified to participants upon disappearance of the array. We show that high probabilistic cueing facilitates T1 detection and improves the corresponding sensitivity index (d'). In contrast, retention and conscious report of secondary targets (T2) improves when the probabilistic cueing of T1 position is poor. These results suggest that uncertainty in the upcoming position of primary targets boosts the strength of memory traces evoked by secondary targets and improves the possibility that traces of secondary targets gain full access to conscious processing.

EEG Correlates of Preparatory Orienting, Contextual Updating, and Inhibition of Sensory Processing in Left Spatial Neglect.

Studies with event-related potentials have highlighted deficits in the early phases of orienting to left visual targets in right-brain-damaged patients with left spatial neglect (N+). However, brain responses associated with preparatory orienting of attention, with target novelty and with the detection of a match/mismatch between expected and actual targets (contextual updating), have not been explored in N+. Here in a study in healthy humans and brain-damaged patients of both sexes we demonstrate that frontal activity that reflects supramodal mechanisms of attentional orienting (Anterior Directing Attention Negativity, ADAN) is entirely spared in N+. In contrast, posterior responses that mark the early phases of cued orienting (Early Directing Attention Negativity, EDAN) and the setting up of sensory facilitation over the visual cortex (Late Directing Attention Positivity, LDAP) are suppressed in N+. This uncoupling is associated with damage of parietal-frontal white matter. N+ also exhibit exaggerated novelty reaction to targets in the right side of space and reduced novelty reaction for those in the left side (P3a) together with impaired contextual updating (P3b) in the left space. Finally, we highlight a drop in the amplitude and latency of the P1 that over the left hemisphere signals the early blocking of sensory processing in the right space when targets occur in the left one: this identifies a new electrophysiological marker of the rightward attentional bias in N+. The heterogeneous effects and spatial biases produced by localized brain damage on the different phases of attentional processing indicate relevant functional independence among their underlying neural mechanisms and improve the understanding of the spatial neglect syndrome.SIGNIFICANCE STATEMENT Our investigation answers important questions: are the different components of preparatory orienting (EDAN, ADAN, LDAP) functionally independent in the healthy brain? Is preparatory orienting of attention spared in left spatial neglect? Does the sparing of preparatory orienting have an impact on deficits in reflexive orienting and in the assignment of behavioral relevance to the left space? We show that supramodal preparatory orienting in frontal areas is entirely spared in neglect patients though this does not counterbalance deficits in preparatory parietal-occipital activity, reflexive orienting, and contextual updating. This points at relevant functional dissociations among different components of attention and suggests that improving voluntary attention in N+ might be behaviorally ineffective unless associated with stimulations boosting the response of posterior parietal-occipital areas.

Expectancy modulates pupil size both during endogenous orienting and during re-orienting of spatial attention: A study with isoluminant stimuli.

We have recently demonstrated that when endogenous orienting of spatial attention is guided by central directional cues that reliably predict the position of lateral targets. Pupil Dilation (PDil) is higher as compared with directional cues that do not predict target position. These findings were interpreted as reflecting different levels of Locus Coeruleus-Noradrenergic activity during endogenous orienting. In contrast to this, we were not able to highlight reliable differences between PDil responses to infrequent invalid targets that are associated with predictive cues and frequent invalid targets that are associated with non-predictive ones. These null findings might have been due to the spurious influence of transitory changes in luminance at the moment of target presentation or to the short time window used for the analysis of target-related changes in PDil. Here, we re-explored cue- and target-related changes in PDil using cue and target stimuli that were kept isoluminant to their background and long lasting cue and target periods for data recording and analysis. We fully replicate our previous cue-related results and, in addition, we demonstrate that infrequent invalid targets in the predictive experimental condition evoke larger PDil as compared with frequent ones. Analyses with Linear Mixed Models highlighted that both during the cue and target period, higher levels of PDil were associated with slower reaction times. These findings confirm that PDil is a reliable marker of the expectancy components of endogenous cue-related and exogenous target-related orienting of spatial attention.

The Attentional-SNARC effect 16 years later: no automatic space-number association (taking into account finger counting style, imagery vividness, and learning style in 174 participants).

The Attentional-SNARC effect (Att-SNARC) originally described by Fischer et al. (Nat Neurosci 6(6):555, 2003), consists of faster RTs to visual targets in the left side of space when these are preceded by small-magnitude Arabic cues at central fixation and by faster RTs to targets in the right side of space when these are preceded by large-magnitude cues. Verifying the consistency and reliability of this effect is important, because the effect would suggest an inherent association between the representation of space and that of number magnitude, while a number of recent studies provided no positive evidence in favour of the Att-SNARC and the inherency of this association (van Dijck et al. in Q J Exp Psychol 67(8):1500-1513, 2014; Zanolie and Pecher in Front Psychol 5:987, 2014; Fattorini et al. in Cortex 73:298-316, 2015; Pinto et al. in Cortex, DOI:10.1016/j.cortex.2017.12.015, 2018). Here, we re-analysed Att-SNARC data that we have collected in 174 participants over different studies run in our laboratory. Most important, in a subsample of 79 participants, we also verified whether the strength and reliability of the Att-SNARC is eventually linked inter-individual variations in finger counting style, imagery vividness, and verbal/visual learning style. We found no evidence for the Att-SNARC effect or for the influence of finger counting style, imagery vividness, and learning style on its direction or consistency. These results confirm no inherent link between orienting of spatial attention and representation of number magnitudes. We propose that this link is rather determined by the joint use of spatial and number magnitude or parity codes in the performance of the numerical task at hand.

Endobronchial amphotericin B to treat hemoptysis in an inoperable patient with aspergillosis.

A 37-year-old man presented with chronic cavitary pulmonary aspergillosis and hemoptysis refractory to systemic antifungal therapy with voriconazole and bronchial artery embolization. Surgical excision was unfeasible due to the patient's refusal of blood transfusions. Ten sessions of intracavitary instillation of amphotericin B via flexible bronchoscopy were then performed. Hemoptysis cessation and aspergilloma resolution were achieved, with no toxicity or side effects, and the clinical benefits were sustained at six months of follow-up.

The time course of the spatial representation of 'past' and 'future' concepts: New evidence from the STEARC effect.

Humans use space to think of and communicate the flow of time. This spatial representation of time is influenced by cultural habits so that in left-to-right reading cultures, short durations and past events are mentally positioned to the left of long durations and future events. The STEARC effect (Space Temporal Association of Response Codes) shows a faster classification of short durations/past events with responses on the left side of space and of long durations/future events with responses on the right side. We have recently showed that during the classification of time durations, space is a late heuristic of time because in this case, the STEARC appears only when manual responses are slow, not when they are fast. Here, we wished to extend this observation to the semantic classification of words as referring to the 'past' or the 'future'. We hypothesised that the semantic processing of 'past' and 'future' concepts would have engaged slower decision processes than the classification of short versus long time durations. According to dual-route models of conflict tasks, if the task-dependent classification/decision process were to proceed relatively slowly, then the effects of direct activation of culturally preferred links between stimulus and response (S-R), i.e., past/left and future/right in the case of the present task, should attain higher amplitudes before the instruction-dependent correct response is selected. This would imply that, at variance with the faster classification of time durations, during the slower semantic classification of time concepts, in incongruent trials, the direct activation of culturally preferred S-R links should introduce significant reaction time (RT) costs and a corresponding STEARC at the fastest manual responses in the experiment too. The study's results confirmed this hypothesis and showed that in the classification of temporal words, the STEARC also increased as a function of the length of RTs. Taken together, the results from sensory duration and semantic classification STEARC tasks show that the occurrence, strength and time course of the STEARC varies significantly as a function of the speed and level of cognitive processing required in the task.

Temperament and probabilistic predictive coding in visual-spatial attention.

Cholinergic (Ach), Noradrenergic (NE), and Dopaminergic (DA) pathways play an important role in the regulation of spatial attention. The same neurotransmitters are also responsible for inter-individual differences in temperamental traits. Here we explored whether biologically defined temperamental traits determine differences in the ability to orient spatial attention as a function of the probabilistic association between cues and targets. To this aim, we administered the Structure of Temperament Questionnaire (STQ-77) to a sample of 151 participants who also performed a Posner task with central endogenous predictive (80 % valid/20 % invalid) or non-predictive cues (50 % valid/50 % invalid). We found that only participants with high scores in Plasticity and Intellectual Endurance showed a selective abatement of attentional costs with non-predictive cues. In addition, stepwise regression showed that costs in the non-predictive condition were negatively predicted by scores in Plasticity and positively predicted by scores in Probabilistic Thinking. These results show that stable temperamental characteristics play an important role in defining the inter-individual differences in attentional behaviour, especially in the presence of different probabilistic organisations of the sensory environment. These findings emphasize the importance of considering temperamental and personality traits in social and professional environments where the ability to control one's attention is a crucial functional skill.

How time gets spatial: factors determining the stability and instability of the mental time line.

Left-to-right readers classify faster past events with motor responses on the left side of space and future events with responses on the right side. This suggests a left-to-right spatial organization in the mental representation of time. Here, we show that the significance and reliability of this representation are linked to the joint use of temporal and spatial codes in the task at hand. In a first unimanual Go/No-Go Implicit Association Test (IAT), attending selectively to "past" or to "future" words did not activate corresponding "left" or "right" spatial concepts and vice versa. In a second IAT, attending to both temporal (i.e., "past" and "future") words and spatial targets (i.e., "left" and "right") pointing arrows produced faster responses for congruent rather than incongruent combinations of temporal and spatial concepts in task instructions (e.g., congruent = "Go with past words and left-pointing arrows"; incongruent = "Go with past words and right-pointing arrows"). This effect increased markedly in a STEARC task where spatial codes defined the selection between "left-side" and "right-side" button presses that were associated with "past" and "future" words. Two control experiments showed only partial or unreliable space-time congruency effects when (a) participants attended to superordinate semantic codes that included both spatial "left"/"right" or temporal "past/future" subordinate codes; (b) a primary speeded response was assigned to one dimension (e.g., "past vs. future") and a nonspeeded one to the other dimension (e.g., "left" vs. "right"). These results help to define the conditions that trigger a stable and reliable spatial representation of time-related concepts.

Space is a late heuristic of elapsing time: New evidence from the STEARC effect.

To get a concrete representation of its intangible flow, culture frames elapsing time along spatially oriented mental or graphical lines, which are organised according to reading habits, from left to right in western cultures. One of the strongest evidence for this spatial representation of time is the STEARC effect (Spatial-Temporal Association of Response Codes), which consists of faster coding of "short" durations with motor responses in the left side of space and of "long" durations with responses in the right side. Here, we investigated the STEARC as a function of response speed in two different experiments in healthy participants. Surprisingly, in both sub- and supra-second ranges, we found the STEARC only when decisions on time durations were slow, while no spatial representation of time was present with fast decisions. This first demonstrates that space slowly takes over faster non-spatial processing of time flow and that it is possible to empirically separate the behavioural manifestations of the non-spatial and the nurtured spatial mechanisms of time coding.

The Emerging Role of Senotherapy in Cancer: A Comprehensive Review.

Senotherapy, a promising therapeutic strategy, has drawn a lot attention recently due to its potential for combating cancer. Senotherapy refers to the targeting of senescent cells to restore tissue homeostasis and mitigate the deleterious effects associated with senescence. Senolytic drugs represent a promising avenue in cancer treatment, with the potential to target and modulate senescent cells to improve patient outcomes. The review highlights the intricate interplay between the senescence-associated secretory phenotype (SASP) and the tumor microenvironment, emphasizing the role of senescent cells in promoting chronic inflammation, immune evasion, and tumor-cell proliferation. It then explores the potential of senotherapy as a novel strategy for cancer therapy. This review addresses the emerging evidence on the combination of senotherapy with conventional cancer treatments, such as chemotherapy and immunotherapy.

Frailty in Portuguese Older Patients From Convalescence Units: A Cross-Sectional Study.

Background: Frailty is a common geriatric syndrome, associated with adverse clinical outcomes. Nevertheless, studies about frailty in continuous care units are scarce. In this way, this study aimed to assess frailty in older patients admitted in convalescence units (CUs) and analyze its association with demographic, social and clinical characteristics. Methods: This cross-sectional study included older patients admitted in eight CUs of the Integrated Continued Care National Network in Northern Portugal. Exclusion criteria were: total ≤ 11 in Glasgow coma scale, < 10 in mini-mental state examination or being unable to communicate. A comprehensive protocol was administered to assess health-related and lifestyle characteristics, comorbidity, dependence on activities of daily living (ADL), depressive and anxiety symptoms, cognition, and socio-familial risk. Frailty was assessed by Tilburg frailty indicator (TFI). Results: A sample of 165 patients was included (median age = 77; 65% female), with 80% classified as frail, mostly women (P = 0.002), widowed (P = 0.016), shorter (P = 0.005), feeling more tired (P < 0.005) and with less energy (P < 0.005). Also, these patients reported more vision problems (P = 0.006), difficulties in walking (P = 0.022) and climbing stairs (P = 0.029), pain (P = 0.004), falls (P = 0.046), non-alcohol use (P = 0.043) and non-physical activity (P = 0.032). Frail patients had a higher number of previous hospitalizations (P = 0.018), comorbidity (P = 0.006), dependence on instrumental (P < 0.001) and basic (P = 0.006; P < 0.001) ADL, depressive (P < 0.001) and anxiety (P = 0.002) symptoms. After adjusting for covariates, frailty was associated with females (adjusted odds ratio (aOR) = 4.45, P = 0.011), vascular disease (aOR = 4.40, P = 0.040), vision problems (aOR = 10.85, P < 0.001), high dependency on instrumental ADL (aOR = 0.74, P = 0.002), and depressive symptoms (aOR = 1.37, P = 0.001). Conclusions: Frailty is high among older patients in CUs, particularly in females, with vascular disease, vision problems, instrumental ADL dependence and depressive symptoms. Thus, frailty should be screened, and preventive and therapeutic measures should be considered for those at high risk, in order to minimize possible negative consequences.

Multimorbidity Profile of COVID-19 Deaths in Portugal during 2020.

BACKGROUND: COVID-19 is caused by SARS-CoV-2 infection and has reached pandemic proportions. Since then, several clinical characteristics have been associated with poor outcomes. This study aimed to describe the morbidity profile of COVID-19 deaths in Portugal. METHODS: A study was performed including deaths certificated in Portugal with "COVID-19" (ICD-10: U07.1 or U07.2) coded as the underlying cause of death from the National e-Death Certificates Information System between 16 March and 31 December 2020. Comorbidities were derived from ICD-10 codes using the Charlson and Elixhauser indexes. The resident Portuguese population estimates for 2020 were used. RESULTS: The study included 6701 deaths (death rate: 65.1 deaths/100,000 inhabitants), predominantly males (72.1). The male-to-female mortality ratio was 1.1. The male-to-female mortality rate ratio was 1.2; however, within age groups, it varied 5.0-11.4-fold. COVID-19 deaths in Portugal during 2020 occurred mainly in individuals aged 80 years or older, predominantly in public healthcare institutions. Uncomplicated hypertension, uncomplicated diabetes mellitus, congestive heart failure, renal failure, cardiac arrhythmias, dementia, and cerebrovascular disease were observed among COVID-19 deceased patients, with prevalences higher than 10%. A high prevalence of zero morbidities was registered using both the Elixhauser and Charlson comorbidities lists (above 40.2%). Nevertheless, high multimorbidity was also identified at the time of COVID-19 death (about 36.5%). Higher multimorbidity levels were observed in men, increasing with age up to 80 years old. Zero-morbidity prevalence and high multimorbidity prevalences varied throughout the year 2020, seemingly more elevated in the mortality waves' peaks, suggesting variation according to the degree of disease incidence at a given period. CONCLUSIONS: This study provides detailed sociodemographic and clinical information on all certificated deaths from COVID-19 in Portugal during 2020, showing complex and extreme levels of morbidity (zero-morbidity vs. high multimorbidity) dynamics during the first year of the pandemic in Portugal.

Selective blood-brain barrier permeabilization of brain metastases by a type 1 receptor-selective tumor necrosis factor mutein.

BACKGROUND: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumor development and heterogeneously permeable at later stages. Intravenous injection of tumor necrosis factor (TNF) selectively induces BBB permeabilization at sites of brain micrometastasis, in a TNF type 1 receptor (TNFR1)-dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilization, while minimizing potential toxicity. METHODS: A library of human TNF muteins (mutTNF) was generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilizing activity in vitro, potential immunogenicity, and circulatory half-life. The permeabilizing ability of the most promising variant was assessed in vivo in a model of brain metastasis. RESULTS: The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity, and permeabilization of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilization was induced selectively at sites of micrometastases in vivo, with a time window of ≥24 hours and enabling delivery of agents within a therapeutically relevant range (0.5-150 kDa), including the clinically approved therapy, trastuzumab. CONCLUSIONS: We have developed a clinically translatable mutTNF that selectively opens the BBB at micrometastatic sites, while leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist.

European Portuguese Version of the Clinical Frailty Scale: Translation, Cultural Adaptation and Validation Study.

INTRODUCTION: This study aims to describe the translation and adaptation of the European Portuguese Clinical Frailty Scale and assess its convergent validity and test-retest reliability. MATERIAL AND METHODS: This validation study included a sample of elderly people admitted in two convalescence units from the National Network of Integrated Continuous Care in Northern Portugal and followed in two outpatient clinics of social solidarity institutions. Convergent validity of the scale was evaluated, against Tilburg Frailty Indicator. Test-retest reliability, sensitivity and specificity were assessed. RESULTS: Overall, 51 patients were included (mean age = 78 years old). The Clinical Frailty Scale identified 43.1% patients with frailty. Kappa values for test-retest reliability (non-frail/frail) was 1.00. The intraclass correlation coefficient for the 9-point total scale was 0.999. A correlation between Clinical Frailty Scale and Tilburg Frailty Indicator was also found (rs = 0.683; p < 0.001). The Cohen's kappa coefficient was 0.423 in the agreement analysis between these scales. The results for sensitivity and specificity defined that 62.0% of patients were true positives and 81.8% true negatives. The scale accuracy determined by the receiver operating characteristics curve analysis was 0.782. DISCUSSION: This scale showed an excellent test-retest reliability. Robust results on convergent validity were also achieved, with a moderate correlation and agreement with the Tilburg Frailty Indicator, showing good sensitivity and accuracy, as well as high specificity. CONCLUSION: This version has an excellent test-retest reliability and good convergent validity, and is both a reliable and valid test for application in clinical practice for assessing Portuguese elderly population admitted in convalescence units and outpatient clinics.

Introdução: Este estudo tem como objetivo descrever a tradução e adaptação da versão Portuguesa da Clinical Frailty Scale e avaliar a validade convergente e fiabilidade teste-reteste. Material e Métodos: Este estudo de validação incluiu idosos internados em duas unidades de convalescença da Rede Nacional de Cuidados Continuados Integrados no Norte de Portugal e seguidos em consulta de ambulatório de Instituições de solidariedade social. A validade convergente desta escala foi avaliada, comparando-a com o Tilburg Frailty Indicator. A fiabilidade teste-reteste, sensibilidade e especificidade foram testadas. Resultados: Foram incluídos 51 doentes (idade média = 78 anos). A escala identificou 43,1% idosos com fragilidade. Na fiabilidade teste-reteste foi encontrado um kappa = 1 (não-frágil/frágil). O coeficiente de correlação intraclasse para o total da escala de nove pontos foi 0,999. Foi encontrada uma correlação entre a Clinical Frailty Scale e o Tilburg Frailty Indicator (rs = 0,683; p < 0,001). O coeficiente Cohen's kappa foi 0,423 na análise da concordância entre estas escalas. Os resultados de sensibilidade e especificidade definiram que 62,0% dos pacientes eram verdadeiros positivos e 81,8% verdadeiros negativos. A precisão, determinada pela análise da curva de características receptor-operador, foi de 0,782. Discussão: A escala revelou uma excelente fiabilidade teste-reteste, bons resultados de validade convergente, boa correlação e um nível de concordância moderado com o Tilburg Frailty Indicator, demonstrando boa sensibilidade, precisão, e elevada especificidade. Conclusão: Esta versão da escala demonstra excelente fiabilidade teste-reteste e boa validade convergente, sendo um teste fiável e válido para aplicação na prática clínica na avaliação da população idosa portuguesa admitida em unidades de convalescença e em unidades de ambulatório.

How to trigger and keep stable directional Space-Number Associations (SNAs).

Humans are prone to mentally organise the ascending series of integers according to reading habits so that in western cultures small numbers are positioned to the left of larger ones on a mental number line. Despite 140 years since seminal observations by Sir Francis Galton (Galton, 1880a, b), the functional mechanisms that give rise to directional Space-Number Associations (SNAs) remain elusive. Here, we contrasted three different experimental conditions, each including a different version of a Go/No-Go task with intermixed numerical and arrow-targets (Shaki and Fischer, 2018; Pinto et al., 2019a). We show that directional SNAs are not "all or none" phenomena. We demonstrate that SNAs get progressively less noisy and more stable the more contrasting small/large magnitude-codes and contrasting left/right spatial-codes are explicitly and fully combined in the task set. The analyses of the time-course of space-number congruency effects showed that both the absence and presence of the SNA were independent of the speed of reaction times. In agreement with our original proposal (Aiello et al., 2012), these findings show that conceptualising the ascending series of integers in spatial terms depends on the use of spatial codes in the numerical task at hand rather than on the presence of an inherent spatial dimension in the semantic representation of numbers. This evidence suggests that directional SNAs, like the SNARC effect, are secondary to the primary transfer of spatial response codes to number stimuli, rather than deriving from a primary congruency or incongruence between independent spatial-response and spatial-number codes.