The Impact of Congestive Heart Failure on Outcomes in Patients Hospitalized With Preeclampsia.

INTRODUCTION: The purpose of this study was to determine the prevalence of congestive heart failure (CHF) among patients admitted with preeclampsia as well as to analyze the independent association of CHF with in-hospital outcomes among women with preeclampsia. METHODS: Data were obtained from the National (Nationwide) Inpatient Sample (NIS) from January 2016 to December 2019. We assessed the independent association of CHF with outcomes in patients admitted with preeclampsia. Predictors of mortality in patients admitted with preeclampsia were also analyzed. RESULTS: Women with preeclampsia in the United States between 2016 and 2019 were included in our analysis. A total of 256,010 cases were isolated, comprising 1150 patients with preeclampsia and CHF (0.45%). Multivariate analysis demonstrated that CHF in patients with preeclampsia was independently associated with several outcomes, among them cardiac arrest (adjusted OR (aOR) 4.635, p=0.004), ventricular tachycardia (aOR 17.487, p<0.001), pulmonary embolism (aOR 6.987, p<0.001), and eclampsia (aOR 2.503, p=0.011). Conversely, we found CHF to be protective against postpartum hemorrhage (aOR 0.665, p=0.003). Among the predictors of mortality in preeclampsia are age (aOR 1.062, p=0.022), Asian or Pacific Islander race (aOR 4.695, p=0.001), and CHF (aOR 25.457, p<0.001).  Conclusions: In a large cohort of patients admitted with preeclampsia, we found the prevalence of CHF to be 0.45%. CHF was associated with several adverse outcomes as well as increased length of stay.

Real-life evidence about the use of intravenous brivaracetam in urgent seizures: The BRIV-IV study.

PURPOSE: Urgent seizures are a medical emergency for which new therapies are still needed. This study evaluated the use of intravenous brivaracetam (IV-BRV) in an emergency setting in clinical practice. METHODS: BRIV-IV was a retrospective, multicenter, observational study. It included patients ≥18 years old who were diagnosed with urgent seizures (including status epilepticus (SE), acute repetitive seizures, and high-risk seizures) and who were treated with IV-BRV according to clinical practice in 14 hospital centers. Information was extracted from clinical charts and included in an electronic database. Primary effectiveness endpoints included the rate of IV-BRV responder patients, the rate of patients with a sustained response without seizure relapse in 12 h, and the time between IV-BRV administration and clinical response. Primary safety endpoints were comprised the percentage of patients with adverse events and those with adverse events leading to discontinuation. RESULTS: A total of 156 patients were included in this study. The mean age was 57.7 ± 21.5 years old with a prior diagnosis of epilepsy for 57.1% of patients. The most frequent etiologies were brain tumor-related (18.1%) and vascular (11.2%) epilepsy. SE was diagnosed in 55.3% of patients. The median time from urgent seizure onset to IV treatment administration was 60.0 min (range: 15.0-360.0), and the median time from IV treatment to IV-BRV was 90.0 min (range: 30.0-2400.0). Regarding dosage, the mean bolus infusion was 163.0 ± 73.0 mg and the mean daily dosage was 195.0 ± 87.0 mg. A total of 77.6% of patients responded to IV-BRV (66.3% with SE vs. 91% other urgent seizures) with a median response time of 30.0 min (range: 10.0-60.0). A sustained response was achieved in 62.8% of patients. However, adverse events were reported in 14.7%, which were predominantly somnolence and fatigue, with 4.5% leading to discontinuation. Eighty-six percent of patients were discharged with oral brivaracetam. CONCLUSION: IV-BRV in emergency settings was effective, and tolerability was good for most patients. However, a larger series is needed to confirm the outcomes.

Value contribution of cenobamate for the treatment of Focal-Onset Seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through reflective Multi-Criteria Decision Analysis (MCDA).

INTRODUCTION: Epilepsy is one of the most common neurological conditions worldwide. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, despite the availability of many anti-seizure medications, including the latest options, called third-generation anti-seizure medications (ASMs), approximately 40% of people with epilepsy present drug-resistant epilepsy (DRE). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. In a chronic disease with a portfolio of available ASMs, the decision to introduce a new therapeutic alternative must follow a holistic evaluation of value provided. Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine the value contribution of a treatment in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. PURPOSE: The aim of this study was to determine the relative value contribution of cenobamate in the treatment of FOS in patients with DRE compared with third-generation ASMs using reflective MCDA-based methodology. METHODS: A systematic literature review (combining biomedical databases and grey literature sources) was performed to populate the Evidence and Value: Impact on DEcisionMaking (EVIDEM) MCDA framework adapted to determine what represents value in the management of FOS in patients with DRE in Spain. The study was conducted in two phases. The first took place in 2021 with a multi-stakeholder group of eight participants. The second phase was conducted in 2022 with a multi-stakeholder group of 32 participants. Participants were trained in MCDA methodology and scored four evidence matrices (cenobamate vs. brivaracetam, vs. perampanel, vs. lacosamide and vs. eslicarbazepine acetate). Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: DRE is considered a very severe condition associated with many important unmet needs, mainly with regard to the lack of more effective treatments to achieve the ultimate goal of treatment. Compared to third-generation ASMs, cenobamate is perceived to have a better efficacy profile based on improvements in responder rate and seizure freedom. Regarding safety, it is considered to have a similar profile to alternatives and a positive quality-of-life profile. Cenobamate results in lower direct medical costs (excluding pharmacological) and indirect costs. Overall, cenobamate is regarded as providing a high therapeutic impact and supported by high-quality evidence. CONCLUSIONS: Based on reflective MCDA methodology and stakeholders' experience in clinical management of epilepsy in Spain, cenobamate is perceived as a value-added option for the treatment of patients with DRE when compared with third-generation ASMs.

IL-4, IL-10, CCL2 and TGF-ß as potential biomarkers for severity in Plasmodium vivax malaria.

Cytokines and chemokines are immune response molecules that display diverse functions, such as inflammation and immune regulation. In Plasmodium vivax infections, the uncontrolled production of these molecules is thought to contribute to pathogenesis and has been proposed as a possible predictor for disease complications. The objective of this study was to evaluate the cytokine profile of P. vivax malaria patients with different clinical outcomes to identify possible immune biomarkers for severe P. vivax malaria. The study included patients with non-severe (n = 56), or severe (n = 50) P. vivax malaria and healthy controls (n = 50). Patient plasma concentrations of IL-4, IL-2, CXCL10, IL-1ß, TNF-α, CCL2, IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, CXCL8 and active TGF-ß1 were determined through flow cytometry. The levels of several cytokines and chemokines, CXCL10, IL-10, IL-6, IL-4, CCL2 and IFN-γ were found to be significantly higher in severe, compared to non-severe P. vivax malaria patients. Severe thrombocytopenia was positively correlated with IL-4, CXCL10, IL-6, IL-10 and IFN-γ levels, renal dysfunction was related to an increase in IL-2, IL-1ß, IL-17A and IL-8, and hepatic impairment with CXCL10, MCP-1, IL-6 and IFN-γ. A Lasso regression model suggests that IL-4, IL-10, CCL2 and TGF-ß might be developed as biomarkers for severity in P. vivax malaria. Severe P. vivax malaria patients present specific cytokine and chemokine profiles that are different from non-severe patients and that could potentially be developed as biomarkers for disease severity.

Perampanel for the treatment of patients with myoclonic seizures in clinical practice: Evidence from the PERMIT study.

PURPOSE: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. METHODS: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. RESULTS: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months. CONCLUSION: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.

Ecosystem health, ecosystem services, and the well-being of humans and the rest of nature.

An ecosystem is healthy if it is active, maintains its organization and autonomy over time, and is resilient to stress. Healthy ecosystems provide human well-being via ecosystem services, which are produced in interaction with human, social, and built capital. These services are affected by different ecosystem stewardship schemes. Therefore, society should be aiming for ecosystem health stewardship at all levels to maintain and improve ecosystem services. We review the relationship between ecosystem health and ecosystem services, based on a logic chain framework starting with (1) a development or conservation policy, (2) a management decision or origin of the driver of change, (3) the driver of change itself, (4) the change in ecosystem health, (5) the change in the provision of ecosystem services, and (6) the change in their value to humans. We review two case studies to demonstrate the application of this framework. We analyzed 6,131 records from the Ecosystem Services Valuation Database (ESVD) and found that in approximately 58% of the records data on ecosystem health were lacking. Finally, we describe how the United Nations' System of Environmental-Economic Accounting (SEEA) incorporates ecosystem health as part of efforts to account for natural capital appreciation or depreciation at the national level. We also provide recommendations for improving this system.

Hospital Arrival and Functional Outcome after Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with an ominous outcome influenced by the time to hospital presentation. OBJECTIVE: This study aims to identify the factors that influence an early hospital arrival after ICH and the relationship with outcome. METHODS: In this multicenter registry, patients with confirmed ICH on CT scan and well-known time of symptoms onset were studied. Clinical data, arrival conditions, and prognostic scores were analyzed. Multivariate models were built to find independent predictors of < 6 h arrival (logistic regression) and in-hospital death (Cox proportional-hazards model). RESULTS: Among the 473 patients analyzed (51% women, median age 63 years), the median delay since onset to admission was 6.25 h (interquartile range: 2.5-24 h); 7.8% arrived in < 1 h, 26.3% in < 3 h, 45.3% in < 6 h, and 62.3% in < 12 h. The in-hospital, 30-day and 90-day case fatality rates were 28.8%, 30.0%, and 32.6%, respectively. Predictors of arrival in < 6 h were hypertension treatment (odds ratios [OR]: 1.675, 95% confidence intervals [CI]: 1.030-2.724), ≥ 3 years of schooling (OR: 1.804, 95% CI: 1.055-3.084), and seizures at ICH onset (OR: 2.416, 95% CI: 1.068-5.465). Predictors of death (56.9% neurological) were systolic blood pressure > 180 mmHg (hazards ratios [HR]: 1.839, 95% CI: 1.031-3.281), ICH score ≥ 3 (HR: 2.302, 95% CI: 1.300-4.074), and admission Glasgow Coma Scale < 8 (HR: 4.497, 95% CI: 2.466-8.199). Early arrival was not associated with outcome at discharge, 30 or 90 days. CONCLUSIONS: In this study, less than half of patients with ICH arrived to the hospital in < 6 h. However, early arrival was not associated with the short-term outcome in this data set.

Liver and kidney dysfunction, hypoglycemia, and thrombocytopenia in Plasmodium vivax malaria patients at a Colombian Northwest region.

Plasmodium vivax has high morbidity, it is the Plasmodium species with the greatest worldwide distribution, and its ability to trigger severe symptoms is currently recognized. The present study aims to compare the clinical and epidemiological characteristics of patients with P. vivax malaria, with and without complication criteria, in an endemic area for malaria transmission in northwest Colombia. A descriptive cross-sectional study was carried out between 2017 and 2019, patients with P.vivax severe malaria (n = 50), non-severe malaria (n = 56) and healthy controls (n = 50) were included. Sociodemographic, clinical, hematological, and biochemical characteristics were analyzed. Clinical follow-up was carried out in a group of patients with severe malaria. The statistical analysis was carried out in GraphPad Prism; the Chi-square test analyzed categorical variables, comparisons of variables for the three groups were carried out by the Kruskal-Wallis test and comparison between two groups by the Mann-Whitney test. A multiple correspondence analysis described the relationship between variables, which was carried out through the R software. One hundred fifty-six individuals were linked to the study, 76 women and 80 men, between 3 and 71 years old. For 50% of the patients, it was their first malaria episode; 42% of the patients classified with severe malaria required hospitalization, compared to 7.1% of the patients with non-severe malaria. Parasitaemia was similar in both clinical groups; however, 10% of severe patients presented high parasitemia, between 20,000-135,000. The most frequent clinical characteristics in patients with severe malaria were severe thrombocytopenia in 54%, hypoglycemia in 48%, and liver and kidney failure in 30%. Biochemical and hematological parameters returned to normal in 90% of the patients with severe malaria on the third day after starting treatment. Thrombocytopenia, hypoglycemia, and liver and kidney dysfunctions were the most frequent P. vivax malaria complications in this study. Hemoglobin concentration and parasite count were not related to the clinical condition of patients. Thrombocytopenia was the most frequent finding in patients with malaria, and its severity presented an inverse relationship with the number of previous malaria episodes.

Clasificación de empresas ganaderas doble propósito por calidad y canales de comercialización de la leche en el Caribe colombiano / Dual purpose farms classify according quality and milk marketing channels on the colombian Caribbean

RESUMEN Una leche de excelente calidad debe presentar altos porcentajes de proteína, grasa y sólidos totales, bajos recuentos de mesófilos y de células somáticas y estar libres de inhibidores y sustancias extrañas, para asegurar su inocuidad. El objetivo del presente estudio fue realizar una clasificación de empresas ganaderas de doble propósito, con base a la calidad de la leche y sus canales de comercialización, en una subregión del medio Sinú, en el Caribe colombiano. El tipo de estudio fue descriptivo transversal. Se determinaron variables fisicoquímicas, microbiológicas de la leche y de la sanidad de la ubre, y, por medio de una encuesta, se analizaron parámetros zootécnicos, para establecer factores de manejo. Igualmente, mediante un análisis de componentes principales y correspondencias múltiples, se categorizó la productividad y la competitividad, de acuerdo con los parámetros de calidad de la leche cruda. La mayoría de las empresas ganaderas fueron consideradas de mediana extensión con ordeño manual y almacenamiento de la leche en cantinas. El porcentaje de vacas en ordeño no fue alto y una tercera parte de los productores manifestaron mayores ingresos, por ventas diferentes a la leche. Se determinó que la mayor competitividad, se presentó en las empresas ganaderas que realizan excelentes prácticas de manejo y se asoció con altos índices de calidad y productivos. En consecuencia, es necesario implementar las buenas prácticas ganaderas, para aumentar la competitividad.

ABSTRACT An excellent quality milk must have high protein, fat and total solids percentages, low mesophilic and somatic cells counts, and to be free of inhibitor and foreign substances in order to ensure its safety. The objective of this study was to classify the dual-purpose farms based on its milk quality and its marketing channels in a subregion of the middle Sinu in the colombian Caribbean. The study type was descriptive cross sectional. Physicochemical, microbiological variables and udder health were analyzed. Zootechnical parameters were evaluated in order to stablish the manage factors. Equally, through an analysis of mayor compounds and multiple matches the productivity and competitiveness of the farms was categorized based on row milk quality parameters. Most livestock companies were considered as medium length with manual milking and milk storage in canteens. The percentage of cows in milking are not high and a third part of the producer manifested higher income by sales other than milk. It was determined that the higher competitiveness associated with higher quality and productivity indexes occurred in farms where best management practices were implemented. It is necessary to implement good livestock practices to increase the competitiveness.

Deep learning-level melanoma detection by interpretable machine learning and imaging biomarker cues.

SIGNIFICANCE: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics. AIM: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration. APPROACH: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves. RESULTS: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs. CONCLUSIONS: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology.

Bacteria from industrial waste: potential producers of polyhydroxyalkanoates (PHAs) in Manizales, Colombia.

Polymers are currently used in the industry as raw material, yet they are rapidly eliminated and largely contaminate the environment. To address this issue, there is a special interest in biodegradable polymers, namely, polyhydroxyalkanoates (PHAs), produced by microorganisms. This study identifies PHA-producing bacteria from two industrial wastewaters of Manizales, Colombia. The samples were cultured in mineral salt medium with glucose as the carbon source in the presence of Nile red stain. The fluorescent colonies were independently transferred to another medium and assessed through fluorescence microscopy with Nile blue stain. The fluorescent strains under Nile blue staining were purified in Nutrient Agar, and their morphological and microbiological characteristics were determined. The bacteria positive for red-orange fluorescence were purified in Nutrient Agar medium, and molecular analyses were performed by PCR amplification of a 650-bp fragment of the 16S ribosomal DNA gene. The bacteria were also assessed in terms of PHA production. We confirmed the identity of 12 out of 14 PHA-positive strains, which belonged to the following genera: Bacillus, Lactococcus, Citrobacter, Enterobacter, and Acinetobacter. Five of the isolates (Enterobacter cloacae, Enterobacter sp., Enterobacter ludwigii, Bacillus thuringiensis, and Bacillus safensis) are promising strains for PHA production, with production values ranging from 0.360 to 0.9960 g/L. Bacteria that produce more than 0.3 g/L are considered useful for the industrial manufacture of bioplastic. We recommend performing large-scale studies on these strains to assess their use for the industrial production of biopolymers, allowing to generate high-impact bioconversion processes of industrial interest.

Ab initio Determination of the Phase Diagram of CO_{2} at High Pressures and Temperatures.

The experimental study of the CO_{2} phase diagram is hampered by strong kinetic effects leading to wide regions of metastability and to large uncertainties in the location of some phase boundaries. Here, we determine CO_{2}'s thermodynamic phase boundaries by means of ab initio calculations of the Gibbs free energy of several solid phases of CO_{2} up to 50 Gigapascals. Temperature effects are included in the quasiharmonic approximation. Contrary to previous suggestions, we find that the boundary between molecular forms and the nonmolecular phase V has, indeed, a positive slope and starts at 21.5 GPa at T=0 K. A triple point between phase IV, V, and the liquid phase is found at 35 GPa and 1600 K, indicating a broader region of stability for the nonmolecular form than previously thought. The experimentally determined boundary line between CO_{2}-II and CO_{2}-IV phases is reproduced by our calculations, indicating that kinetic effects do not play a major role in that particular transition. Our results also show that CO_{2}-III is stabilized at high temperature and its stability region coincides with the P-T conditions where phase VII has been reported experimentally; instead, phase II is the most stable molecular phase at low temperatures, extending its region of stability to every P-T condition where phase III is reported experimentally.

Dermoscopy of primary cutaneous B- and T-cell lymphomas and pseudolymphomas presenting as solitary nodules and tumors: a case-control study with histopathologic correlation.

BACKGROUND: Primary cutaneous lymphomas (PCLs) and pseudolymphomas presenting as single pink-red nodules/tumors are highly unspecific and include a wide differential diagnosis. OBJECTIVE: To describe the dermoscopic characteristics of PCL/pseudolymphoma. METHODS: In this retrospective, case-control study, we evaluated the dermoscopic features of patients with solitary PCL/pseudolymphoma tumors and compared them to a control group of non-lymphomatous, nonpigmented, solitary tumors (e.g., basal cell carcinoma, amelanotic melanoma, etc). RESULTS: We included 14 patients with PCL/pseudolymphomas and 35 controls. T-cell and B-cell lymphoma proportions were 28.6% (n = 4) and 71.4% (n = 10), respectively. Compared to controls, most lymphomas presented dermoscopically with orange color (71.4% vs. 14.2%, P < 0.001), follicular plugs (85% vs. 2.8%, P < 0.001), and as  organized lesions (85% vs. 31.4%, P = 0.001). Coexistence of orange color and follicular plugs had an odds ratio (OR) of 2.8 (P < 0.001), highly suggestive of PCL . The kappa index for independent observers was 0.66, 0.49, 0.43 for orange background, follicular plugs, and organized lesion, respectively. Histopathologic correlation was performed in six PCL cases and showed dense diffuse and perifollicular lymphocytic infiltrate in all cases and keratin plugs in five of six cases, possibly correlating with the orange color and the follicular plugs, respectively. CONCLUSION: Primary cutaneous lymphomas/pseudolymphomas present with characteristic dermoscopic findings irrespective of immunohistochemical subtype.

MONOZEB: Long-term observational study of eslicarbazepine acetate monotherapy.

AIM: The aim of the study was to evaluate the effectiveness and tolerability of eslicarbazepine acetate (ESL) when used as monotherapy for 1 year or more in routine clinical use in patients with focal seizures in epilepsy clinics in Spain. METHODS: This is a retrospective, observational, noninterventional study. Eligible patients were aged ≥18 years, had focal seizures, and started on ESL ≥1 year before database closure. Primary endpoint was the following: proportion seizure-free for ≥6 months at 1 and 2 years. Secondary endpoints included retention on ESL monotherapy at 1 and 2 years, seizure frequency change, seizure worsening, and side effects. Other analyses included seizure freedom from baseline to 1 and 2 years and outcomes in special populations. RESULTS: Four hundred thirty-five patients were included (127 on first-line monotherapy and 308 converting to ESL monotherapy): median daily dose was 800 mg at all time points; 63.2% were seizure-free at 1 year, 65.1% at 2 years, and 50.3% for the entire follow-up. Mean duration of ESL monotherapy was 66.7 months; retention was 88.0% at 1 year and 81.9% at 2 years. Mean reduction in seizure frequency was 75.5% at last visit. Over the entire follow-up, seizure worsening was seen in 22 patients (5.1%), side effects in 28.0%, considered severe in 1.8%, and leading to discontinuation in 5.7%. Dizziness, hyponatremia (sodium <135 mEq/l), and somnolence were the most frequent side effects. Outcomes in special populations (patients aged ≥65 years and those with psychiatric history or learning difficulty) were consistent with the overall population. CONCLUSIONS: Patients with focal seizures taking ESL monotherapy had excellent retention, high seizure-free rates, and good tolerability up to 2 years.

BRIVA-LIFE-A multicenter retrospective study of the long-term use of brivaracetam in clinical practice.

OBJECTIVES: Evaluate long-term effectiveness and tolerability of brivaracetam in clinical practice in patients with focal epilepsy. MATERIALS AND METHODS: This was a multicenter retrospective study. Patients aged ≥16 years were started on brivaracetam from November 2016 to June 2017 and followed over 1 year. Data were obtained from medical records at 3, 6 and 12 months after treatment initiation for evaluation of safety- and seizure-related outcomes. RESULTS: A total of 575 patients were included in analyses; most had been treated with ≥4 lifetime antiepileptic drugs. Target dosage was achieved by 30.6% of patients on the first day. Analysis of primary variables at 12 months revealed that mean reduction in seizure frequency was 36.0%, 39.7% of patients were ≥50% responders and 17.5% were seizure-free. Seizure-freedom was achieved by 37.5% of patients aged ≥65 years. Incidence of adverse events (AEs) and psychiatric AEs (PAEs) was 39.8% and 14.3%, respectively, and discontinuation due to these was 8.9% and 3.7%, respectively. Somnolence, irritability, and dizziness were the most frequently reported AEs. At baseline, 228 (39.7%) patients were being treated with levetiracetam; most switched to brivaracetam (dose ratio 1:10-15). Among those who switched because of PAEs (n = 53), 9 (17%) reported PAEs on brivaracetam, and 3 (5.7%) discontinued because of PAEs. Tolerability was not highly affected among patients with learning disability or psychiatric comorbidity. CONCLUSIONS: In a large population of patients with predominantly drug-resistant epilepsy, brivaracetam was effective and well-tolerated; no unexpected AEs occurred over 1 year, and the incidence of PAEs was lower compared with levetiracetam.

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

OBJECTIVE: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). METHODS: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. RESULTS: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. SIGNIFICANCE: In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.

Balancing selfishness and norm conformity can explain human behavior in large-scale prisoner's dilemma games and can poise human groups near criticality.

Cooperation is central to the success of human societies as it is crucial for overcoming some of the most pressing social challenges of our time; still, how human cooperation is achieved and may persist is a main puzzle in the social and biological sciences. Recently, scholars have recognized the importance of social norms as solutions to major local and large-scale collective action problems, from the management of water resources to the reduction of smoking in public places to the change in fertility practices. Yet a well-founded model of the effect of social norms on human cooperation is still lacking. Using statistical-physics techniques and integrating findings from cognitive and behavioral sciences, we present an analytically tractable model in which individuals base their decisions to cooperate both on the economic rewards they obtain and on the degree to which their action complies with social norms. Results from this parsimonious model are in agreement with observations in recent large-scale experiments with humans. We also find the phase diagram of the model and show that the experimental human group is poised near a critical point, a regime where recent work suggests living systems respond to changing external conditions in an efficient and coordinated manner.

Engineering Small Molecule Responsive Split Protein Kinases.

The over 500 human protein kinases are estimated to phosphorylate at least one-third of the proteome. This posttranslational modification is of paramount importance to intracellular signaling and its deregulation is linked to numerous diseases. Deciphering the specific cellular role of a protein kinase of interest remains challenging given their structural similarity and potentially overlapping activity. In order to exert control over the activity of user-defined kinases and allow for understanding and engineering of complex signal transduction pathways, we have designed ligand inducible split protein kinases. In this approach, protein kinases are dissected into two fragments that cannot spontaneously assemble and are thus inactive. The two kinase fragments are attached to chemical inducers of dimerization (CIDs) that allow for ligand induced heterodimerization and concomitant activation of kinase activity.

Definición de nanomateriales para Colombia / Definition of Nanomateriais for Colombia / Definição de nanomateriais para a Colômbia

Debido a la creciente producción y uso de nanomateriales para actividades de investigación y desarrollo en Colombia, es necesario establecer una definición del término nanomaterial que facilite la toma de decisiones en torno a iniciativas de carácter regulatorio y de normatividad. Se presenta la definición de nanomateriales para Colombia que ha adoptado el Consejo Nacional Asesor de Nanociencia y Nanotecnología adscrito a la Red Colombiana de Nanociencia y Nanotecnología.

Due to the increasing production and use of nanomaterials in research and development activities in Colombia, it is necessary to define the nanomaterial term in order to facilitate decision-making process regarding initiatives with a regulatory or normative character. This article presents the nanomaterials definition that has been adopted by the National Advisory Council for Nanoscience and Nanotechnology, a Colombian Network of Nanoscience and Nanotechnology.

Dada a crescente produção e utilização de nanomateriais para a pesquisa e desenvolvimiento na Colombia, é urgente estabelecer uma definição do termo de nanomaterial para facilitar a tomada de decisão sobre iniciativas na regulamentação e as leis. É apresentada uma definição de nanomateriais para a Colombia que aprovou o Conselho Consultivo Nacional de Nanociência e Nanotecnologia ligado à Rede Colombiana de Nanociência e Nanotecnologia.

Small molecule gated split-tyrosine phosphatases and orthogonal split-tyrosine kinases.

Protein kinases phosphorylate client proteins, while protein phosphatases catalyze their dephosphorylation and thereby in concert exert reversible control over numerous signal transduction pathways. We have recently reported the design and validation of split-protein kinases that can be conditionally activated by an added small molecule chemical inducer of dimerization (CID), rapamycin. Herein, we provide the rational design and validation of three split-tyrosine phosphatases (PTPs) attached to FKBP and FRB, where catalytic activity can be modulated with rapamycin. We further demonstrate that the orthogonal CIDs, abscisic acid and gibberellic acid, can be used to impart control over the activity of split-tyrosine kinases (PTKs). Finally, we demonstrate that designed split-phosphatases and split-kinases can be activated by orthogonal CIDs in mammalian cells. In sum, we provide a methodology that allows for post-translational orthogonal small molecule control over the activity of user defined split-PTKs and split-PTPs. This methodology has the long-term potential for both interrogating and redesigning phosphorylation dependent signaling pathways.