Towards optimized methodological parameters for maximizing the behavioral effects of transcranial direct current stimulation.

Introduction: Transcranial direct current stimulation (tDCS) administers low-intensity direct current electrical stimulation to brain regions via electrodes arranged on the surface of the scalp. The core promise of tDCS is its ability to modulate brain activity and affect performance on diverse cognitive functions (affording causal inferences regarding regional brain activity and behavior), but the optimal methodological parameters for maximizing behavioral effects remain to be elucidated. Here we sought to examine the effects of 10 stimulation and experimental design factors across a series of five cognitive domains: motor performance, visual search, working memory, vigilance, and response inhibition. The objective was to identify a set of optimal parameter settings that consistently and reliably maximized the behavioral effects of tDCS within each cognitive domain. Methods: We surveyed tDCS effects on these various cognitive functions in healthy young adults, ultimately resulting in 721 effects across 106 published reports. Hierarchical Bayesian meta-regression models were fit to characterize how (and to what extent) these design parameters differentially predict the likelihood of positive/negative behavioral outcomes. Results: Consistent with many previous meta-analyses of tDCS effects, extensive variability was observed across tasks and measured outcomes. Consequently, most design parameters did not confer consistent advantages or disadvantages to behavioral effects-a domain-general model suggested an advantage to using within-subjects designs (versus between-subjects) and the tendency for cathodal stimulation (relative to anodal stimulation) to produce reduced behavioral effects, but these associations were scarcely-evident in domain-specific models. Discussion: These findings highlight the urgent need for tDCS studies to more systematically probe the effects of these parameters on behavior to fulfill the promise of identifying causal links between brain function and cognition.

Anatomical categorization of isolated non-focal dystonia: novel and existing patterns using a data-driven approach.

According to expert consensus, dystonia can be classified as focal, segmental, multifocal, and generalized, based on the affected body distribution. To provide an empirical and data-driven approach to categorizing these distributions, we used a data-driven clustering approach to compare frequency and co-occurrence rates of non-focal dystonia in pre-defined body regions using the Dystonia Coalition (DC) dataset. We analyzed 1,618 participants with isolated non-focal dystonia from the DC database. The analytic approach included construction of frequency tables, variable-wise analysis using hierarchical clustering and independent component analysis (ICA), and case-wise consensus hierarchical clustering to describe associations and clusters for dystonia affecting any combination of eighteen pre-defined body regions. Variable-wise hierarchical clustering demonstrated closest relationships between bilateral upper legs (distance = 0.40), upper and lower face (distance = 0.45), bilateral hands (distance = 0.53), and bilateral feet (distance = 0.53). ICA demonstrated clear grouping for the a) bilateral hands, b) neck, and c) upper and lower face. Case-wise consensus hierarchical clustering at k = 9 identified 3 major clusters. Major clusters consisted primarily of a) cervical dystonia with nearby regions, b) bilateral hand dystonia, and c) cranial dystonia. Our data-driven approach in a large dataset of isolated non-focal dystonia reinforces common segmental patterns in cranial and cervical regions. We observed unexpectedly strong associations between bilateral upper or lower limbs, which suggests that symmetric multifocal patterns may represent a previously underrecognized dystonia subtype.

Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

A contrast set mining based approach for cancer subtype analysis.

The task of detecting common and unique characteristics among different cancer subtypes is an important focus of research that aims to improve personalized therapies. Unlike current approaches mainly based on predictive techniques, our study aims to improve the knowledge about the molecular mechanisms that descriptively led to cancer, thus not requiring previous knowledge to be validated. Here, we propose an approach based on contrast set mining to capture high-order relationships in cancer transcriptomic data. In this way, we were able to extract valuable insights from several cancer subtypes in the form of highly specific genetic relationships related to functional pathways affected by the disease. To this end, we have divided several cancer gene expression databases by the subtype associated with each sample to detect which gene groups are related to each cancer subtype. To demonstrate the potential and usefulness of the proposed approach we have extensively analysed RNA-Seq gene expression data from breast, kidney, and colon cancer subtypes. The possible role of the obtained genetic relationships was further evaluated through extensive literature research, while its prognosis was assessed via survival analysis, finding gene expression patterns related to survival in various cancer subtypes. Some gene associations were described in the literature as potential cancer biomarkers while other results have been not described yet and could be a starting point for future research.

Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis.

Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.

Acute bioaccumulation and chronic toxicity of olivine in the marine amphipod Gammarus locusta.

Active atmospheric carbon dioxide removal (CDR) is needed at a gigaton scale in the next decades to keep global warming below 1.5 °C. Coastal enhanced silicate weathering (CESW) aims to increase natural ocean carbon sequestration via chemical weathering of finely ground olivine (MgxFe(1-x)SiO4) rich rock dispersed in dynamic coastal environments. However, the environmental safety of the technique remains in question due to the high Ni and Cr content of olivine. Therefore, we investigated the short term bioaccumulation and chronic toxicity of olivine in the marine amphipod Gammarus locusta. Acute 24-h olivine exposure resulted in significant grain size dependent olivine ingestion and subsequent Ni and Cr accumulation in tissues. Thousands of small (mainly ≤ 10  µm) olivine grains were ingested by G. locusta, but their importance for trace metal bioaccumulation requires additional research. Most olivine grains were egested within 24 h. Chronic 35-day olivine (3-99 µm) exposure reduced amphipod survival, growth, and reproduction, likely as a result of metal induced oxidative stress and disturbance of major cation homeostasis. Amphipod reproduction was significantly reduced at olivine concentrations of 10% w/w and higher. In the context of ecological risk assessment, application of an arbitrary assessment factor of 100 to the highest no observed effect concentration of 1% w/w olivine yields a very low predicted no-effect concentration (PNEC) of 0.01% w/w olivine. This low PNEC value highlights the urgent need for additional marine olivine toxicity data to accurately assess the environmentally safe scale of coastal enhanced weathering for climate change mitigation.

Structure-Based Drug Discovery with Deep Learning.

Artificial intelligence (AI) in the form of deep learning has promise for drug discovery and chemical biology, for example, to predict protein structure and molecular bioactivity, plan organic synthesis, and design molecules de novo. While most of the deep learning efforts in drug discovery have focused on ligand-based approaches, structure-based drug discovery has the potential to tackle unsolved challenges, such as affinity prediction for unexplored protein targets, binding-mechanism elucidation, and the rationalization of related chemical kinetic properties. Advances in deep-learning methodologies and the availability of accurate predictions for protein tertiary structure advocate for a renaissance in structure-based approaches for drug discovery guided by AI. This review summarizes the most prominent algorithmic concepts in structure-based deep learning for drug discovery, and forecasts opportunities, applications, and challenges ahead.

Derivaciones arteriales temporales en los programas de entrenamiento para los cirujanos generales.

The skills development to address vascular trauma by general surgeons is important in hospitals in countries with a lack of vascular surgeons, so we agree the implementation of training programs in vascular surgery basic techniques for general surgeons. In Peru, through an exploratory survey, 43 public hospitals have at least one vascular surgeon, of which 20 are located in Metropolitan Lima, and 14 of the 26 regions of Peru have at least one public institution with vascular surgery capabilities. We recommend the incorporation of the transient arterial shunt technique as an alternative to vascular anastomosis due to its security and feasibility for general surgeons training programs.

Es importante el desarrollo de habilidades por los cirujanos generales para abordar el trauma vascular en los hospitales de países con escaso número de cirujanos vasculares, por lo que coincidimos con la implementación de programas de capacitación en técnicas básicas de cirugía vascular para los cirujanos generales. En Perú, a través de una encuesta exploratoria, encontramos que 43 hospitales públicos cuentan con al menos un cirujano vascular, de los cuales 20 están ubicados en Lima Metropolitana, y 14 de las 26 regiones del Perú cuentan con al menos una institución pública con capacidades en cirugía vascular. Recomendamos la incorporación de la técnica de derivación arterial transitoria como alternativa a la anastomosis vascular debido a su seguridad y factibilidad para los programas de formación de cirujanos generales.

Epidemiological time-trend of amyotrophic lateral sclerosis (ALS) over two decades: The French population-based register of ALS in Limousin (FRALim register).

INTRODUCTION: Population-based registers are key to understanding disease patterns. Taking advantage of the long-standing operation of the French register of amyotrophic lateral sclerosis (ALS) in Limousin (FRALim register), we sought to determine the time trends in incidence, clinical features and survival of ALS patients from 2000 to 2020. METHODS: FRALim register included incident cases through multiple sources of ascertainment. A capture-recapture method was used to assess the exhaustiveness of case ascertainment. Crude and standardized incidences were calculated per 100,000 person-years of follow-up (PYFU). Time-period was divided (period 2000 to 2010 and period 2011 to 2020) to compare incidence rates and clinical features. Survival was analyzed using Kaplan-Meier method. Cox proportional hazards model was performed to calculate hazards for the time periods. RESULTS: Overall, 501 incident cases were identified during 21 years. The overall crude incidence was 3.26 (95% CI 2.97 to 3.55) per 100 000 PYFU. The exhaustiveness of the register was estimated at 98.8% (95% CI 97.4-99.6%) by capture-recapture analysis. Several fluctuations were observed without a consistent trend over the last two decades. The crude and standardized incidences were higher in males than females. The peak of incidence was observed in the 75-79 years age band. Almost one-third of the cases exhibited a bulbar onset. There were significant differences in clinical features between time periods. Four hundred and ninety-one cases were included in the survival analysis. The median survival time from diagnosis was 16.0 months (95% CI 14.3 to 17.7 months). Patients in the last decade experienced a lower risk of dying but the difference did not reach statistical significance (adjusted HR: 0.89 (95% CI 0.73 to 1.08, P=0.229). CONCLUSION: We provided reliable epidemiological data over two decades. We showed that incidence has been relatively stable, while clinical variability was observed. A slight improvement in survival time was found in the last decade but it was not statistically significant. Further quality register data are needed to improve our understanding of ALS epidemiological trends.

Trace element adsorption from acid mine drainage and mine residues on nanometric hydroxyapatite.

Mining Ag, Cu, Pb, and Zn sulfides by flotation produces great volume of residues, which oxidized through time and release acid solutions. Leachates from tailing heaps are a concern due to the risk of surface water pollution. Hydroxyapatite nanoparticles may remove trace elements from acid leachate collected from an oxidized tailing heap (pH ranged 1.69 ± 0.3 to 2.23 ± 0.16; [SO42-] = 58 ± 0.67 to 60.69 ± 0.39 mmol). Based on the batch experiments under standard conditions, the average removal efficiency was 96%, 92%, 86%, and 67% for Cd, Pb, Zn, and Cu, respectively. The Zn adsorption was modeled by the Freundlich equation, but Cd, Cu, and Pb isotherms do not fit to Freundlich nor Lagmuir equations. Adsorption and other mechanisms occur during trace elements removal by hydroxyapatite. In the polymetallic system, trace elements saturate the specific surface of hydroxyapatite in the following order Zn, Cd, Cu, and Pb. The pH values must be higher than 7.5 to adsorb trace elements. The dose of 3.8% of hydroxyapatite to acid mine drainage removed efficiently > 80% of the soluble Fe, Cu, Mn, Zn, Cd, Ni, and Pb: 4020.0, 37.3, 34.8, 432.0, 4.4, 0.7, and 0.11 mg L-1 from leachate A and 3357.1, 46.6, 27.8, 569.0, 4.7, 0.6, and 1.7 from leachate B, respectively. The application of 0.7% of hydroxyapatite decreased the extractable Pb in unoxidized tailing heaps from 272 to 100 mg kg-1. It is likely to use hydroxyapatite to control trace element mobility from mine residues to surrounding soils and surface water.

Phenotypic variability in amyotrophic lateral sclerosis.

Clinically, ALS phenotypes depend on the areas of the body that are affected, the different degrees of involvement of upper and lower motor neurons, the degrees of involvement of other systems, particularly cognition and behavior, and rates of progression. Phenotypic variability of ALS is characteristic and can be declined on the distribution of motor manifestations but also on the presence of extra-motor signs present in a variable manner in ALS patients. Neuropathologically, ALS is defined by the loss of UMN and LMN and the presence of two representative motor neuronal cytoplasmic inclusions, Bunina bodies and 43kDa Transactivation Response DNA Binding Protein (TDP-43) - positive cytoplasmic inclusions. The distribution of cytopathology and neuronal loss in patients is variable and this variability is directly related to phenotypic variability. Key regulators of phenotypic variability in ALS have not been determined. The functional decrement of TDP-43, and region-specific neuronal susceptibility to ALS, may be involved. Due to the selective vulnerability among different neuronal systems, lesions are multicentric, region-oriented, and progress at different rates. They may vary from patient to patient, which may be linked to the clinicopathological variability across patients.

Quantitative phase retrieval with low photon counts using an energy resolving quantum detector.

X-ray phase contrast imaging (PCI) combined with phase retrieval has the potential to improve soft-material visibility and discrimination. This work examined the accuracy, image quality gains, and robustness of a spectral phase retrieval method proposed by our group. Spectroscopic PCI measurements of a physical phantom were obtained using state-of-the-art photon-counting detectors in combination with a polychromatic x-ray source. The phantom consisted of four poorly attenuating materials. Excellent accuracy was demonstrated in simultaneously retrieving the complete refractive properties (photoelectric absorption, attenuation, and phase) of these materials. Approximately 10 times higher SNR was achieved in retrieved images compared to the original PCI intensity image. These gains are also shown to be robust against increasing quantum noise, even for acquisition times as low as 1 s with a low-flux microfocus x-ray tube (average counts of 250 photons/pixels). We expect that this spectral phase retrieval method, adaptable to several PCI geometries, will allow significant dose reduction and improved material discrimination in clinical and industrial x-ray imaging applications.

Gastric carcinoma and renal cell carcinoma as an atypical presentation of multiple primary malignancies: a case report and review of the literature.

BACKGROUND: Gastric carcinoma (GC) with second primary malignancy (SPM) is the most frequent combination within the multiple primary malignancies (MPM) group. The presentation of a GC associated with a synchronized SPM in the kidney is extremely rare and unusual. This study presents a rare case of synchronous tumors, describes the main associated risk factors, and emphasizes the need to rule out SPM. MAIN BODY: We present the case of a 63-year-old Hispanic woman with a history of smoking, weight loss, and gastrointestinal (GI) bleeding. GC was diagnosed by endoscopy, and during her workup for metastatic disease, a synchronous SPM was noted in the left kidney. The patient underwent resection of both tumors with a satisfactory postoperative course. A systematic review of the literature was performed using the Medline/PubMed, Science Direct, Scopus, and Google Scholar databases. A search of the literature yielded 13 relevant articles, in which the following main risk factors were reported: the treatment utilized, the grade and clinical stage, histopathological report, and in some cases survival. It is concluded that advanced age (> 60 years) and smoking are the main associated risk factors. CONCLUSION: Gastric carcinoma is the second most frequent neoplasm of the GI tract and the main neoplasm that presents a SPM. MPM screening is recommended in patients with gastric cancer. The clinical discovery of MPM of renal origin is rare and hence the importance of the current report.

Complicaciones neurológicas en pacientes críticos por SARS-CoV-2 / Neurological complications in critical patients with COVID-19

INTRODUCCIÓN: Nos proponemos analizar las complicaciones neurológicas de los pacientes con infección grave por SARS-CoV-2 que han requerido ingreso en unidad de cuidados intensivos (UCI). PACIENTES Y MÉTODOS: Estudio descriptivo retrospectivo, observacional, de pacientes consecutivos ingresados en UCI por infección respiratoria grave por SARS-CoV-2 desde el 1 de abril hasta el 1 de junio de 2020. RESULTADOS: Registramos 30 pacientes con síntomas neurológicos, 21 hombres (72,40%), edad media: 57,41 años ± 11,61 desviación estándar (DE). Estancia media en UCI: 18,83 ± 14,33 DE. A nivel sindrómico: 28 pacientes (93,33%) con síndrome confusional agudo, 15 (50%) con patología neuromuscular, 5 (16,66%) con cefalea, 4 (13,33%) con patología cerebrovascular y 4 (13,33%) con encefalopatías/encefalitis. Punción lumbar normal en 6 pacientes (20%). La RMN craneal o TAC craneal mostró alteraciones en 20 casos (66,6%). Se realizó EEG en todos los pacientes (100%), alterado en 8 pacientes (26,66%). En 5 de los 15 pacientes con miopatía clínica se ha podido confirmar con ENMG. Hemos encontrado relación entre la mayor edad y los días de ingreso en UCI (p = 0,002; IC95%: 4,032-6,022; OR: 3,594). CONCLUSIONES: La infección grave por COVID-19 afecta mayoritariamente a hombres, similar a lo descrito en otras series. La mitad de nuestros pacientes presenta una miopatía aguda, y casi la totalidad de los pacientes salen de la UCI con síndromes confusionales agudos que evolucionan a una resolución completa, sin correlacionarse con los resultados del EEG o de pruebas de neuroimagen. La mayor edad se asocia con un mayor número de días de estancia en UCI

INTRODUCTION: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. PATIENTS AND METHODS: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. RESULTS: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P = .002; 95%CI: 4.032-6.022; OR: 3,594). CONCLUSIONS: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay

Neurological complications in critical patients with COVID-19. / Complicaciones neurológicas en pacientes críticos por SARS-CoV-2.

INTRODUCTION: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. PATIENTS AND METHODS: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. RESULTS: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P=.002; 95%CI: 4.032-6.022; OR: 3,594). CONCLUSIONS: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay.

Asymmetrical influence of a standard light/dark cycle and constant light conditions on the alanyl-aminopeptidase activity of the left and right retinas in adult male rats.

The retina acts as an independent clock informing the central pacemaker, the suprachiasmatic nucleus, under environmental light conditions, with consequences of such inputs for the central and peripheral nervous system. Differences in the behavior of the left and right retinas depending on environmental light conditions may influence the information projected to the brain hemispheres. The retina possesses neuropeptides that act as neurotransmitters or neuromodulators. Alanyl-aminopeptidase (AlaAP, EC 3.4.11.2) activity regulates some of these neuropeptides and therefore reflects their function. We analyzed AlaAP activity in the left and right retinas of adult male rats at successive time points under standard (12/12 h light/dark cycle) and nonstandard (constant light) conditions. AlaAP activity was measured fluorometrically using alanyl-beta-naphthylamide as the substrate. Under standard conditions, there were no differences in the left or right retina between time points, with the left retina predominating, particularly in the light period. In contrast, under constant light, no left versus right differences were observed, but significant differences between time points appeared. In comparison with standard conditions, constant conditions led to significantly higher AlaAP activity. Considering all the left retina data in comparison with all the right retina data, no correlation was found between the left and right retinas under standard conditions, but a significant positive correlation was observed under constant light. These results demonstrate an asymmetrical response of retinal AlaAP activity to changes in environmental light conditions, which may affect the functions in which the substrates of AlaAP are involved and the information projected to the brain hemispheres.