A Cortical Mechanism Linking Saliency Detection and Motor Reactivity in Rhesus Monkeys.

Sudden and surprising sensory events trigger neural processes that swiftly adjust behavior. To study the phylogenesis and the mechanism of this phenomenon, we trained two male rhesus monkeys to keep a cursor inside a visual target by exerting force on an isometric joystick. We examined the effect of surprising auditory stimuli on exerted force, scalp electroencephalographic (EEG) activity, and local field potentials (LFPs) recorded from the dorsolateral prefrontal cortex. Auditory stimuli elicited (1) a biphasic modulation of isometric force, a transient decrease followed by a corrective tonic increase, and (2) EEG and LFP deflections dominated by two large negative-positive waves (N70 and P130). The EEG potential was symmetrical and maximal at the scalp vertex, highly reminiscent of the human "vertex potential." Electrocortical potentials and force were tightly coupled: the P130 amplitude predicted the magnitude of the corrective force increase, particularly in the LFPs recorded from deep rather than superficial cortical layers. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to salient sensory events.Significance Statement Survival in the natural world depends on an animal's capacity to adapt ongoing behavior to abrupt unexpected events. To study the neural mechanisms underlying this capacity, we trained monkeys to apply constant force on a joystick while we recorded their brain activity from the scalp and the prefrontal cortex contralateral to the hand holding the joystick. Unexpected auditory stimuli elicited a biphasic force modulation: a transient reduction followed by a corrective adjustment. The same stimuli also elicited EEG and LFP responses, dominated by a biphasic wave that predicted the magnitude of the behavioral adjustment. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to unexpected events.

Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice.

BACKGROUND: New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) privileges real-world data. As part of the ongoing HTA, this study aimed to evaluate the effectiveness of palbociclib with aromatase inhibitors (AI) and compare it with the efficacy reported in PALOMA-2. METHODS: A population-based retrospective exposure cohort study was conducted including all patients initiating treatment in Portugal with palbociclib under early access use and registered in the National Oncology Registry. The primary outcome was progression free survival (PFS). Secondary outcomes considered included time to palbociclib failure (TPF), overall survival (OS), time to next treatment (TTNT), and proportion of patients discontinuing treatment due to  adverse events (AEs). The Kaplan-Meier method was used and median, 1- and 2-year survival rates were computed, with two-sided 95% confidence intervals (95%CI). STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were used. RESULTS: There were 131 patients included. Median follow-up was 28.3 months (IQR: 22.7-35.2) and median duration of treatment was 17.5 months (IQR: 7.8-29.1). Median PFS was 19.5 months (95%CI 14.2-24.2), corresponding to a 1-year PFS rate of 67.9% (95%CI 59.2-75.2) and a 2-year PFS rate of 42.0% (95%CI 33.5-50.3). Sensitivity analysis showed median PFS would increase slightly when excluding those not initiating treatment with the recommended dose, raising to 19.8 months (95%CI 14.4-28.9). By considering only patients meeting PALOMA-2 criteria, we could observe a major difference in treatment outcomes, with a mean PFS of 28.8 months (95%CI 19.4-36.0). TPF was 19.8 months (95%CI 14.2-24.9). Median OS was not reached. Median TTNT was 22.5 months (95%CI 18.0-29.8). A total of 14 patients discontinued palbociclib because of AEs (10.7%). CONCLUSIONS: Data suggest palbociclib with AI to have an effectiveness of 28.8 months, when used in patients with overlapping characteristics to those used in PALOMA-2. However, when used outside of these eligibility criteria, namely in patients with less favorable prognosis (e.g., presence of visceral disease), the benefits are inferior, even though still favorable.

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo.

After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis.

Corticocortical Systems Underlying High-Order Motor Control.

Cortical networks are characterized by the origin, destination, and reciprocity of their connections, as well as by the diameter, conduction velocity, and synaptic efficacy of their axons. The network formed by parietal and frontal areas lies at the core of cognitive-motor control because the outflow of parietofrontal signaling is conveyed to the subcortical centers and spinal cord through different parallel pathways, whose orchestration determines, not only when and how movements will be generated, but also the nature of forthcoming actions. Despite intensive studies over the last 50 years, the role of corticocortical connections in motor control and the principles whereby selected cortical networks are recruited by different task demands remain elusive. Furthermore, the synaptic integration of different cortical signals, their modulation by transthalamic loops, and the effects of conduction delays remain challenging questions that must be tackled to understand the dynamical aspects of parietofrontal operations. In this article, we evaluate results from nonhuman primate and selected rodent experiments to offer a viewpoint on how corticocortical systems contribute to learning and producing skilled actions. Addressing this subject is not only of scientific interest but also essential for interpreting the devastating consequences for motor control of lesions at different nodes of this integrated circuit. In humans, the study of corticocortical motor networks is currently based on MRI-related methods, such as resting-state connectivity and diffusion tract-tracing, which both need to be contrasted with histological studies in nonhuman primates.

Two Brains in Action: Joint-Action Coding in the Primate Frontal Cortex.

Daily life often requires the coordination of our actions with those of another partner. After 50 years (1968-2018) of behavioral neurophysiology of motor control, the neural mechanisms that allow such coordination in primates are unknown. We studied this issue by recording cell activity simultaneously from dorsal premotor cortex (PMd) of two male interacting monkeys trained to coordinate their hand forces to achieve a common goal. We found a population of "joint-action cells" that discharged preferentially when monkeys cooperated in the task. This modulation was predictive in nature, because in most cells neural activity led in time the changes of the "own" and of the "other" behavior. These neurons encoded the joint-performance more accurately than "canonical action-related cells", activated by the action per se, regardless of the individual versus interactive context. A decoding of joint-action was obtained by combining the two brains' activities, using cells with directional properties distinguished from those associated to the "solo" behaviors. Action observation-related activity studied when one monkey observed the consequences of the partner's behavior, i.e., the cursor's motion on the screen, did not sharpen the accuracy of joint-action cells' representation, suggesting that it plays no major role in encoding joint-action. When monkeys performed with a non-interactive partner, such as a computer, joint-action cells' representation of the other (non-cooperative) behavior was significantly degraded. These findings provide evidence of how premotor neurons integrate the time-varying representation of the self-action with that of a co-actor, thus offering a neural substrate for successful visuomotor coordination between individuals.SIGNIFICANCE STATEMENT The neural bases of intersubject motor coordination were studied by recording cell activity simultaneously from the frontal cortex of two interacting monkeys, trained to coordinate their hand forces to achieve a common goal. We found a new class of cells, preferentially active when the monkeys cooperated, rather than when the same action was performed individually. These "joint-action neurons" offered a neural representation of joint-behaviors by far more accurate than that provided by the "canonical action-related cells", modulated by the action per se regardless of the individual/interactive context. A neural representation of joint-performance was obtained by combining the activity recorded from the two brains. Our findings offer the first evidence concerning neural mechanisms subtending interactive visuomotor coordination between co-acting agents.

On the cortical connectivity in the macaque brain: A comparison of diffusion tractography and histological tracing data.

Diffusion-weighted magnetic resonance imaging (DW-MRI) tractography is a non-invasive tool to probe neural connections and the structure of the white matter. It has been applied successfully in studies of neurological disorders and normal connectivity. Recent work has revealed that tractography produces a high incidence of false-positive connections, often from "bottleneck" white matter configurations. The rich literature in histological connectivity analysis studies in the macaque monkey enables quantitative evaluation of the performance of tractography algorithms. In this study, we use the intricate connections of frontal, cingulate, and parietal areas, well established by the anatomical literature, to derive a symmetrical histological connectivity matrix composed of 59 cortical areas. We evaluate the performance of fifteen diffusion tractography algorithms, including global, deterministic, and probabilistic state-of-the-art methods for the connectivity predictions of 1711 distinct pairs of areas, among which 680 are reported connected by the literature. The diffusion connectivity analysis was performed on a different ex-vivo macaque brain, acquired using multi-shell DW-MRI protocol, at high spatial and angular resolutions. Across all tested algorithms, the true-positive and true-negative connections were dominant over false-positive and false-negative connections, respectively. Moreover, three-quarters of streamlines had endpoints location in agreement with histological data, on average. Furthermore, probabilistic streamline tractography algorithms show the best performances in predicting which areas are connected. Altogether, we propose a method for quantitative evaluation of tractography algorithms, which aims at improving the sensitivity and the specificity of diffusion-based connectivity analysis. Overall, those results confirm the usefulness of tractography in predicting connectivity, although errors are produced. Many of the errors result from bottleneck white matter configurations near the cortical grey matter and should be the target of future implementation of methods.

A Brief History of the Encoding of Hand Position by the Cerebral Cortex: Implications for Motor Control and Cognition.

Encoding hand position by the cerebral cortex is essential not only for the neural representation of the body image but also for different actions based on eye-hand coordination. These include reaching for visual objects as well as complex movement sequences, such as tea-making, tool use, and object construction, among many others. All these functions depend on a continuous refreshing of the hand position representation, relying on both predictive signaling and afferent information. The hand position influence on neural activity in the parietofrontal system, together with eye position signals, are the basic elements of an eye-hand matrix from which all the above functions can emerge and could be regarded as key features of a network with several entry points, command nodes and outflow pathways, as confirmed by the discovery of a direct parietospinal projection for the control of hand action. The integrity of this system is crucial for daily life, as testified by the consequences of cortical lesions, spanning from severe paralysis to complex forms of apraxia. In this review, I will sketch my personal understanding of the scientific and conceptual trajectory of a line of investigation with many unexpected influences on cortical function and disease, from motor behavior to cognition.

Modulation of Neural Variability in Premotor, Motor, and Posterior Parietal Cortex during Change of Motor Intention.

The time course of neural variability was studied in three nodes of the parieto-frontal system: the dorsal premotor cortex (PMd, area 6), primary motor cortex (MI, area 4), and posterior parietal cortex (PPC, area 5) while monkeys made either direct reaches to visual targets or changed reach direction in response to an unexpected change of target location. These areas are crucial nodes in the distributed control of reaching and their lesion impairs trajectory formation and correction under different circumstances. During unperturbed reaches, neural variability declined before the onset of hand movement in both frontal and parietal cortex. When the original motor intention suddenly changed, neural variability displayed a complex and area-specific modulation because the perturbation of the motor state was signaled earlier in PMd than in MI and PPC. The comparison of perturbed versus unperturbed reaches revealed that, in the time between the onset of correction signal and trajectory change, identical hand movements were associated with different, therefore context-dependent, patterns of neural variability induced by the instruction to change hand movement direction. In PMd, neural variability was higher before the initiation of hand reach than before its correction, thus providing a neural underpinning to the phenomenon that it takes less time to correct than to initiate hand movement. Furthermore, neural variability was an excellent predictor of slow and fast reach corrections because it was lower during the latter than the former. We conclude that the analysis of neural variability can be an important tool for the study of complex forms of motor cognition. SIGNIFICANCE STATEMENT: No single study has been performed on neural variability during update of motor intention across monkey premotor, motor, and posterior parietal cortex. In perturbed reaches, target location changed unexpectedly during reaction time and the correction of hand trajectory required updating the original motor plan. Comparing unperturbed versus perturbed reaches revealed that neural variability displayed a complex context- and area-dependent pattern of modulation because, before trajectory correction, similar initial hand movements were associated with different patterns of variability depending on the instruction signal, and therefore on the future hand path and final destination. Furthermore, neural variability predicted both slow and fast hand movement corrections, also offering a neural underpinning to the phenomenon that it takes less time to correct than to initiate hand movement.

Posterior Parietal Cortex Encoding of Dynamic Hand Force Underlying Hand-Object Interaction.

Major achievements of primate evolution are skilled hand-object interaction and tool use, both in part dependent on parietal cortex expansion. We recorded spiking activity from macaque inferior parietal cortex during directional manipulation of an isometric tool, which required the application of hand forces to control a cursor's motion on a screen. In areas PFG/PF, the activity of ∼ 70% neurons was modulated by the hand force necessary to implement the desired target motion, reflecting an inverse model, rather than by the intended motion of the visual cursor (forward model). The population vector matched the direction and amplitude of the instantaneous force increments over time. When exposed to a new force condition, that obliged the monkey to change the force output to successfully bring the cursor to the final target, the activity of a consistent subpopulation of neurons changed in an orderly fashion and, at the end of a "Wash-out" session, retained memory of the new learned association, at the service of predictive control of force. Our findings suggest that areas PFG/PF represent a crucial node of the distributed control of hand force, by encoding instantaneous force variations and serving as a memory reservoir of hand dynamics required for object manipulation and tool use. This is coherent with previous studies in humans showing the following: (1) impaired adaptation to a new force field under TMS parietal perturbation; (2) defective control of direction of hand force after parietal lesion; and (3) fMRI activation of parietal cortex during object manipulation requiring control of fine hand forces. SIGNIFICANCE STATEMENT: Skilled object manipulation and tool use are major achievements of primate evolution, both largely dependent on posterior parietal cortex (PPC) expansion. Neurophysiological and fMRI studies in macaque and humans had documented a crucial role of PPC in encoding the hand kinematics underlying these functions, leaving to premotor and motor areas the role of specifying the underlying hand forces. We recorded spiking activity from macaque PPC during manipulation of an isometric tool and found that population activity is not only modulated by the dynamic hand force and its change over time, but also retains memory of the exerted force, as a reservoir to guide of future hand action. This suggests parallel parietal encoding of hand dynamics and kinematics during object manipulation.

Diameter, length, speed, and conduction delay of callosal axons in macaque monkeys and humans: comparing data from histology and magnetic resonance imaging diffusion tractography.

Three macaque monkeys and 13 healthy human volunteers underwent diffusion tensor MRI with a 3 Tesla scanner for diffusion tract tracing (DTT) reconstruction of callosal bundles from different areas. In six macaque monkeys and three human subjects, the length of fiber tracts was obtained from histological data and combined with information on the distribution of axon diameter, so as to estimate callosal conduction delays from different areas. The results showed that in monkeys, the spectrum of tract lengths obtained with DTT closely matches that estimated from histological reconstruction of axons labeled with an anterogradely transported tracer. For each sector of the callosum, we obtained very similar conduction delays regardless of whether conduction distance was obtained from tractography or from histological analysis of labeled axons. This direct validation of DTT measurements by histological methods in monkeys was a prerequisite for the computation of the callosal conduction distances and delays in humans, which we had previously obtained by extrapolating the length of callosal axons from that of the monkey, proportionally to the brain volumes in the two species. For this analysis, we used the distribution of axon diameters from four different sectors of the corpus callosum. As in monkeys, in humans the shortest callosal conduction delays were those of motor, somatosensory, and premotor areas; the longer ones were those of temporal, parietal, and visual areas. These results provide the first histological validation of anatomical data about connection length in the primate brain based on DTT imaging.

Impairment of online control of hand and eye movements in a monkey model of optic ataxia.

The parietal mechanisms for online control of hand trajectory were studied by combining single-cell recording and reversible inactivation of superior parietal area 5 (PE/PEc; SPL) of monkeys while these made reaches and saccades to visual targets, when the target position changed unexpectedly. Neural activity was modulated by hand position, speed, and movement direction, and by pre- and/or postsaccadic signals. After bilateral muscimol injection, an increase in the hand reaction- and movement-time toward both the first and second targets was observed. This caused an increase in the time necessary for the trajectory correction, and therefore an elongation of the hand-path toward the first target location. Furthermore, hand trajectories were different in shape than control ones. An elongation of the eye reaction time to both first and second targets was also observed, which could partially explain the deficit of planning and correction of hand movement. These results identify the superior parietal lobule as a crucial node in the online control of hand and eye movement and highlight the role of the eye impairment in the emergence of the reaching disorder so far regarded as the hallmark of optic ataxia.

Meniscectomy leads to early changes in the mineralization distribution of subchondral bone plate.

PURPOSE: It is generally recognized that the subchondral bone plate (SBP) is involved in development of osteoarthritis (OA). However, the pathophysiological significance is not yet clear. The goal of this study is to investigate the extent of the changes that occur in SBP of the tibial plateau in the early stages of experimental OA. METHODS: Forty-three female rabbits were assigned to 5 experimental (n = 8 each group) and one sham group (n = 3). OA was induced by medial meniscectomy in the right knee, the left knee served as control. 2, 4, 8, 12, and 24 weeks after meniscectomy, cartilage damage was evaluated, and bone mineral density (BMD) and mineralization distribution of the SBP was measured by computed tomography osteoabsorptiometry (CT-OAM). RESULTS: Cartilage damage started 2 weeks after meniscectomy with surface roughening. Cartilage defects increased over time. 24 weeks postoperatively, subchondral bone was exposed. As early as 2 weeks after meniscectomy, BMD in the medial tibial plateau decreased significantly. BMD increased again and reached the values of the non-operated knee 12 weeks postoperatively. In addition, already 4 weeks after meniscectomy a significant shift of the density maximum on the medial tibial plateau, which is normally centrally located toward the margin was observed. CONCLUSIONS: In conclusion, the results of this study contribute to the concept of early involvement of the SBP in the development of OA. The hypothesis that changes in the SBP occur simultaneously to cartilage damage was confirmed.

Skin cancer screening: the experience in South Portugal.

BACKGROUND: The number of skin cancer cases and related deaths continues to increase worldwide, including in Portugal. The lack of efficient health care leaves the southern Portuguese population at risk of presenting skin lesions at later stages. An initiative for skin cancer screening and medical care follow-up was created by the nonprofit organization Liga Portuguesa Contra o Cancro - Núcleo Regional do Sul (LPCC-NRS). METHODS: Information was gathered from 4,398 participants in several Southern Portugal regions, from January 2021 to July 2022. Descriptive and lesion risk statistical analyses were applied. RESULTS: Participants' characteristics were described, and risk assessment was performed differentially between premalignant (n = 577) and malignant lesions (n = 176). The main risk factor for both was male gender. From the described suspicious malignant lesions, 31.8% were confirmed (n = 56), among which there were 43 basal cell carcinomas (BCC), 9 cutaneous melanomas (CM), and 4 squamous cell carcinomas (SCC). CONCLUSIONS: Data analysis pointed to a need for improved participant recruitment, especially of male participants, and health literacy assessment in future screenings.

Real-world effectiveness of aromatase inhibitors and fulvestrant in HR+/HER2- advanced breast cancer: a snapshot of the last two years before conventional use of CDK 4/6 inhibitors in a Portuguese institution.

Background: Monotherapy with aromatase inhibitors and fulvestrant were the standard-of-care for hormone receptor-positive (HR+)/human epidermal growth factor receptor-type2 negative (HER2-) advanced breast cancer, before integration of cyclin-dependent kinase 4/6 inhibitors. Effectiveness data is essential for regulatory action, but little is known about real-world use of aromatase inhibitors and fulvestrant. Methods: A retrospective cohort study was conducted resorting to data from a cancer registry to identify adult women with HR+/HER- advanced breast cancer exposed to aromatase inhibitors or fulvestrant (31 May 2017-31 March 2019) at the main oncology hospital in Portugal. Cases were updated with follow-up until death or cut-off (31 March 2021) and pseudoanonymized data extracted. Primary outcome was overall survival (OS) and secondary time to treatment failure (TTF), estimated using survival analysis and compared with published trials. Results: 192 patients were distributed by subgroups according to the medicine. Letrozole: OS 30.8 (95% confidence interval (CI) 20.6-41.4); TTF 11.2 (95%CI 8.7-13.7). Exemestane: OS 22.1 (95%CI 9.7-34.6); TTF 6.0 (95%CI 4.1-7.8). Fulvestrant: OS 21.6 (95%CI 16.5-26.7); TTF 5.6 (95%CI 4.5-6.6). Conclusions: Estimated effectiveness (OS) of letrozole and fulvestrant was, respectively, 3.2-3.5 months lower than reported. The clinical meaning seems uncertain and may be explained a higher proportion of worse prognostic characteristics in patients treated in the real-world.

Epidemiology, Management, and Survival Outcomes of Germ Cell Cancer in Southern Portugal: A Population-Based Study (2008-2012).

INTRODUCTION: Building on previous suboptimal survival results, we aimed to perform a study of the epidemiological status, management, and outcomes of germ cell tumors (GCT) in the Portuguese population. MATERIALS AND METHODS: Retrospective populational study of GCT cases diagnosed between 2008 and 2012 in southern Portugal. Joinpoint regression was used to compute average annual percentage change (AAPC) in incidence rate. ESMO/EAU guidelines served as references to evaluate compliance. Association between compliance with guidelines and hospital GCT case load was performed by generalized estimating equation. Survival was calculated by Kaplan-Meier and prognostic factors by Cox models. RESULTS: The study included 401 GCT male cases. The AAPC was 5.4% (IC 95% 3.3-7.4, P < .001) from 1999 (an earlier cohort published) to 2012. The median time to diagnosis was 63 days (Q25 = 33 days; Q75 = 114 days; IQR = 81 days). For stage II/III the median time to start chemotherapy was 34 days (Q25 = 22 days; Q75 = 56 days; IQR = 22 days). In 86% cases there was noncompliance with guidelines for the orchiectomy report, 6% for staging, 38% for tumor markers evaluation, 20% for treatment and 25% for chemotherapy dose intensity. The 5-year overall survival was 93.8% (95% CI, 91.3%-96.4%). Hospitals that managed ≤ 3 GCT cases/ year had higher odds for noncompliance with guidelines of blood markers, treatment and dose intensity. None of GCT healthcare access and management factors studied were associated with prognosis. CONCLUSIONS: The burden of GCT is rising in Portugal. Although survival has improved, efforts must be made to nationally enhance training and expertise in GCT and support region adapted models of centralization of care.

Neural encoding of musical expectations in a non-human primate.

The appreciation of music is a universal trait of humankind.1,2,3 Evidence supporting this notion includes the ubiquity of music across cultures4,5,6,7 and the natural predisposition toward music that humans display early in development.8,9,10 Are we musical animals because of species-specific predispositions? This question cannot be answered by relying on cross-cultural or developmental studies alone, as these cannot rule out enculturation.11 Instead, it calls for cross-species experiments testing whether homologous neural mechanisms underlying music perception are present in non-human primates. We present music to two rhesus monkeys, reared without musical exposure, while recording electroencephalography (EEG) and pupillometry. Monkeys exhibit higher engagement and neural encoding of expectations based on the previously seeded musical context when passively listening to real music as opposed to shuffled controls. We then compare human and monkey neural responses to the same stimuli and find a species-dependent contribution of two fundamental musical features-pitch and timing12-in generating expectations: while timing- and pitch-based expectations13 are similarly weighted in humans, monkeys rely on timing rather than pitch. Together, these results shed light on the phylogeny of music perception. They highlight monkeys' capacity for processing temporal structures beyond plain acoustic processing, and they identify a species-dependent contribution of time- and pitch-related features to the neural encoding of musical expectations.

Chemical decontamination of methamphetamine and ephedrine using an activated peroxide-containing cleaning solution.

Manufacture and recreational use of methamphetamine can result in widespread chemical contamination throughout a property. Hydrogen peroxide (H2O2)-based cleaning products have shown success against a number of chemical contaminants including agents of chemical warfare, and biological contaminants such as anthrax. They are considered to be environmentally friendly and economically viable and, as such, are used by many companies within the methamphetamine decontamination industry. The oxidative decontamination of methamphetamine and ephedrine hydrochloride was investigated in this current study, employing a commercially available H2O2-based decontamination product, Bio-Oxygen® Chem Decon. Methamphetamine and ephedrine were observed to degrade following pseudo-first order kinetics of (1.9 ± 0.4) × 10-2 min-1 and (2.2 ± 0.3) × 10-2 min-1, respectively. Major oxidation products identified through GC-MS analyses were phenylacetone oxime (from methamphetamine) and benzaldehyde (from ephedrine). LC-MS analysis revealed the presence of a number of N-oxygenated intermediates which allowed for the elucidation of an N-oxidation decomposition pathway reminiscent of flavin-containing monooxygenase enzymes. Using this information, further targeted research can be performed to understand the behaviour and persistence of these reaction products and accurate assessments can be achieved to estimate their impact on the exposure risks associated with chemical decontamination of amphetamine-type stimulants (ATS).

The Effect of Timeliness of Care on Lung Cancer Survival - A Population-Based Approach.

Background: Timeliness of care is an important dimension of healthcare quality but it's unclear whether it improves clinical outcomes in lung cancer (LC) patients. Objectives: This study aims to analyze treatment patterns, time-to-treatment (TTT) and the impact of treatment timeliness (TT) in overall survival (OS) of patients diagnosed with LC in 2009-2014 in a population-based registry from Southern Portugal. Materials and Methods: We estimated median TTT for overall population, treatment type and stage. The impact of treatment and TT on five-year OS was analyzed using the Kaplan-Meier method and Cox regression modelling to determine the hazard ratio (HR) of death associated with treatment and TT. Results: From the 11,308 cases diagnosed, 61.7% received treatment. Treatment rate decreased with increasing stage from 88% in stage I to 66.1% in stage IV. Overall median TTT was 49 days (IQR: 28-88) and 43.3% received TT. Surgery had a longer TTT than radiotherapy and systemic treatment. Patients in earlier stages had lower TT rates and longer TTT compared to more advanced, 24.7% and 80 days in stage I versus 51.3% and 42 days in stage IV (p < 0.0001). OS was 14.9% for total population and 19.6% and 7.1% for patients with and without treatment registered, respectively. TT had no observed impact on OS for stages I/II but a negative effect for stages III/IV. Relative to treated, the adjusted mortality risk was higher in untreated patients (HR = 2.240; 95%CI: 2.293-2.553). Contrary to treatment, TT had a negative impact on survival, with 11.3% in timely vs. 21.5% in untimely treated. Compared to untimely treated, the risk of death in TT patients was 46.6% higher (HR = 1.465; 95%CI: 1.381-1.555). Conclusions: LC survival is highly dependent on early diagnosis and adequate treatment. Time-to-treatment was longer than recommended for all treatment types but particularly for surgery. Overall TT results were paradoxical, as better survival was observed in patients untimely treated. The factors associated with TT were not possible to analyze and its impact on patient outcomes remains unclear. However, it is important to assess quality-of-care to improved LC management.

The parietal lobe evolution and the emergence of material culture in the human genus.

Traditional and new disciplines converge in suggesting that the parietal lobe underwent a considerable expansion during human evolution. Through the study of endocasts and shape analysis, paleoneurology has shown an increased globularity of the braincase and bulging of the parietal region in modern humans, as compared to other human species, including Neandertals. Cortical complexity increased in both the superior and inferior parietal lobules. Emerging fields bridging archaeology and neuroscience supply further evidence of the involvement of the parietal cortex in human-specific behaviors related to visuospatial capacity, technological integration, self-awareness, numerosity, mathematical reasoning and language. Here, we complement these inferences on the parietal lobe evolution, with results from more classical neuroscience disciplines, such as behavioral neurophysiology, functional neuroimaging, and brain lesions; and apply these to define the neural substrates and the role of the parietal lobes in the emergence of functions at the core of material culture, such as tool-making, tool use and constructional abilities.

A view-based decision mechanism for rewards in the primate amygdala.

Primates make decisions visually by shifting their view from one object to the next, comparing values between objects, and choosing the best reward, even before acting. Here, we show that when monkeys make value-guided choices, amygdala neurons encode their decisions in an abstract, purely internal representation defined by the monkey's current view but not by specific object or reward properties. Across amygdala subdivisions, recorded activity patterns evolved gradually from an object-specific value code to a transient, object-independent code in which currently viewed and last-viewed objects competed to reflect the emerging view-based choice. Using neural-network modeling, we identified a sequence of computations by which amygdala neurons implemented view-based decision making and eventually recovered the chosen object's identity when the monkeys acted on their choice. These findings reveal a neural mechanism in the amygdala that derives object choices from abstract, view-based computations, suggesting an efficient solution for decision problems with many objects.