Analysis of recent land management initiatives in Nicaragua from the perspective of the "ecosystem approach".

In the world there are approximately 608 million farms, of which 84% are small farms and produce 35% of the food of the world population. Training programs have been promoted by different organizations to achieve a more sustainable and efficient agricultural practice. Within this context, this article has classified a set of smallholders located in central Nicaragua with regard to how they apply Land Use Management Initiatives (LUMI). The aim is to outline their weaknesses and strengths and thus identify key elements that can contribute to improving soil resource management. We focus on the LUMI carried out in Nicaragua in the municipalities of El Tuma-La Dalia, El Cuá and Waslala between 1992 and 2022. To conduct this study, eight LUMI were identified and analysed, and 25 indicators linked to the Malawi Principles were extracted and selected for the design of a survey in order to collect land use management information from 455 farms in the study area. Simple random sampling was used to select the farms. Subsequently, the collected data were analysed using descriptive statistics and Multivariate Analysis techniques. The results reveal that in the study area, the LUMI incorporate between one and five Malawi Principles. The multivariate analysis techniques employed identified three clusters of farms, with either Active, Moderate or Improvable ecosystem management. The study area as a whole displays strengths in social participation, local capacity building, soil and environmental conservation practices, with the farm as the main source of income. Weaknesses lie in the fact that indicators referring to household income and productivity are less frequent. In terms of farm management, the results revealed that combined male and female management was similar in percentage to male-only management. The results highlight the need to continue with the implementation of environmental goals linked to the design of initiatives that promote productivity, income and gender equity in farm management in an integrated manner. At the same time, existing local capacities for sustainable soil and ecosystem management should be brought together and strengthened.

Specific afterdischarge properties can enhance the clinical utility of electrical stimulation mapping during intracranial monitoring.

OBJECTIVE: Extraoperative electrical cortical stimulation (ECS) facilitates defining the seizure onset zone (SOZ) and eloquent cortex. The clinical relevance of stimulation-induced afterdischarges (ADs) is not well defined. METHODS: Fifty-five patients who underwent intracranial electroencephalogram evaluations with ECS were retrospectively identified. ADs were identified in these recordings and categorized by pattern, location, and association with stimulation-induced seizures. RESULTS: ADs were generated in 1774/9285 (19%) trials. Rhythmic spikes and irregular ADs within the stimulated bipolar contact pair were predictive of location within the SOZ compared to non-epileptogenic/non-irritative cortex (rhythmic spikes OR 2.24, p = 0.0098; irregular OR 1.39; p = 0.013). ADs immediately preceding stimulated seizures occurred at lower stimulation intensity thresholds compared to other stimulations (mean 2.94 ± 0.28 mA vs. 4.16 ± 0.05 mA respectively; p = 0.0068). CONCLUSIONS: Changes in AD properties can provide clinically relevant data in extraoperative stimulation mapping. SIGNIFICANCE: Although not exclusive to the SOZ, the generation of rhythmic spikes may suggest that a stimulation location is within the SOZ, while decreased stimulation intensity thresholds eliciting ADs may alert clinicians to a heightened probability of seizure generation with subsequent stimulation.

Single-neuronal elements of speech production in humans.

Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.

DREDge: robust motion correction for high-density extracellular recordings across species.

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

Women's wheelchair basketball lineup analysis at the Tokyo 2020 paralympic games: game related statistics explaining team sport performance.

Introduction: Performance analysis through game-related statistics in wheelchair basketball (WB) has focused mainly on the study of the individual efficiency of players according to their functional classification. However, there is little evidence focusing on lineup performances (five players on court) and their composition. Thus, the objective of present study was to analyze the efficiency of the women's WB lineups used during the Tokyo 2020 Paralympic Games (PG) and to determine the variables that best discriminated the lineup performances according to the final point differential. Methods: The sample comprised 507 lineups used in the 31 games by the 10 national teams during the competition. Fifty-one different lineup types (LTs) were categorized. A discriminant analysis was carried out to compare the lineups with a positive and negative point difference according to the game type (balanced and unbalanced games). Results: It was found that LTs 16 (1-1.5-2.5-4-4.5), 47 (1-2-2.5-4-4.5) and 14 (1-1.5-2.5-4.5-4.5) had the best means of efficiency in field goals (LT 16 = 52%; LT 47 = 44% and LT = 40%), while LT 50 (1-2-3-4-4) obtained the highest mean difference in points (3.67 ± 10.67). The variables that best discriminated winner teams in balanced games were field goal efficiency (SC = 0.55), assists (SC = 0.50) and turnovers (SC = -0.41). Discussion: Field goal efficiency, assists, turnovers and steals are the game-related statistics most associated with the success of a lineup used in balanced games in WB in PG competition; this could be taken into account by coaches when deciding how to compose a given lineup in a moment of the game, to adequately select players from different functional classifications for the final squad and to choose training content related to the indicated game-related statistics, as they explain success at this competition level.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Atlantoaxial instability associated with ALDH18A1 mutation.

We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.

Modified Neuropixels probes for recording human neurophysiology in the operating room.

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson's disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.

ROBUST ONLINE MULTIBAND DRIFT ESTIMATION IN ELECTROPHYSIOLOGY DATA.

High-density electrophysiology probes have opened new possibilities for systems neuroscience in human and non-human animals, but probe motion poses a challenge for downstream analyses, particularly in human recordings. We improve on the state of the art for tracking this motion with four major contributions. First, we extend previous decentralized methods to use multiband information, leveraging the local field potential (LFP) in addition to spikes. Second, we show that the LFP-based approach enables registration at sub-second temporal resolution. Third, we introduce an efficient online motion tracking algorithm, enabling the method to scale up to longer and higher-resolution recordings, and possibly facilitating real-time applications. Finally, we improve the robustness of the approach by introducing a structure-aware objective and simple methods for adaptive parameter selection. Together, these advances enable fully automated scalable registration of challenging datasets from human and mouse.

5-ALA fluorescence-guided resection of a recurrent anaplastic pleomorphic xanthoastrocytoma: illustrative case.

BACKGROUND: 5-aminolevulinic acid (5-ALA)-induced fluorescence of neoplastic tissue is known to occur in a number of high-grade gliomas. This fluorescence helps surgeons maximize safe resection by distinguishing previously indiscernible neoplastic tissue from brain parenchyma. Still, the effectiveness of 5-ALA has not been fully explored for all central nervous system tumors. Consequently, the full spectrum of tumors that would benefit from fluorescence-guided surgery using 5-ALA is unknown. OBSERVATIONS: This report describes successfully utilizing 5-ALA to achieve complete resection of a recurrent anaplastic pleomorphic xanthoastrocytoma (APXA). LESSONS: APXA tumor cells accumulate sufficient amounts of 5-ALA and its fluorescent metabolite to produce visible intraoperative fluorescence. However, further investigation is needed to determine if 5-ALA fluorescent labeling routinely occurs in patients with APXAs.

Targeted Nanoparticle for Co-delivery of HER2 siRNA and a Taxane to Mirror the Standard Treatment of HER2+ Breast Cancer: Efficacy in Breast Tumor and Brain Metastasis.

The first-line treatment of advanced and metastatic human epidermal growth factor receptor type 2 (HER2+) breast cancer requires two HER2-targeting antibodies (trastuzumab and pertuzumab) and a taxane (docetaxel or paclitaxel). The three-drug regimen costs over $320,000 per treatment course, requires a 4 h infusion time, and has many adverse side effects, while achieving only 18 months of progression-free survival. To replace this regimen, reduce infusion time, and enhance efficacy, a single therapeutic is developed based on trastuzumab-conjugated nanoparticles for co-delivering docetaxel and siRNA against HER2 (siHER2). The optimal nanoconstruct has a hydrodynamic size of 100 nm and specifically treats HER2+ breast cancer cells over organ-derived normal cells. In a drug-resistant orthotopic HER2+ HCC1954 tumor mouse model, the nanoconstruct inhibits tumor growth more effectively than the docetaxel and trastuzumab combination. When coupled with microbubble-assisted focused ultrasound that transiently disrupts the blood brain barrier, the nanoconstruct inhibits the growth of trastuzumab-resistant HER2+ BT474 tumors residing in the brains of mice. The nanoconstruct has a favorable safety profile in cells and in mice. Combination therapies have become the cornerstone of cancer treatment and this versatile nanoparticle platform can co-deliver multiple therapeutic types to ensure that they reach the target cells at the same time to realize their synergy.

Determinación del intervalo de referencia para subpoblaciones linfocitarias CD3+, CD4+ y CD8+ y el índice CD4+/CD8+ en la población chilena adulta

Resumen Introducción: En varios estudios se ha documentado la influencia de factores étnicos en la distribución de las subpoblaciones linfocitarias; sin embargo, los intervalos de referencia utilizados en Chile fueron obtenidos de un estudio realizado en Países Bajos el año 1997. Objetivo: Determinar el intervalo de referencia para subpoblaciones linfocitarias CD3+, CD4+ y CD8+, además del índice CD4+/CD8+ en la población chilena. Metodología: Se analizó un total de 200 muestras de sangre total obtenida de hombres y mujeres adultos sanos, utilizando el método establecido por el CLSI estandarizado en el protocolo EP28-A3c desde la etapa pre analítica en adelante. Resultados: Los rangos de referencia para CD3+, CD4+ y CD8+ fueron 54,7-81,6% (789-2732 céls/μL), 28,1-57,7% (447-1703 céls/μL) y 15,1-38,8% (226-996 céls/μL), respectivamente. El índice CD4+/CD8+ fue de 0,84-3,77. Discusión: Los valores de referencia de las subpoblaciones linfocitarias en la población chilena sana son diferentes de los que se usan actualmente en Chile. Estas observaciones muestran datos locales que pudieran tener implicaciones para el tratamiento de la infección por VIH, y los rangos de referencia encontrados en este estudio pudieran ser usados para entender la situación local de algunos pacientes. Conclusiones: Otros estudios deberán ser realizados para confirmar estas observaciones dada la falta de datos previos y debido a que este es el primer estudio en población chilena.

Abstract Background: Several studies have documented the influence of ethnic factors on the distribution of lymphocyte subpopulations; however, the reference intervals used in Chile were obtained from a study carried out in the Netherlands in 1997. Aim: To determine the reference interval for CD3+, CD4+ and CD8+ lymphocyte subpopulations, as well as the CD4+/CD8+ index in the Chilean population. Methods: A total of 200 whole blood samples obtained from healthy adult men and women were analyzed using the method established by CLSI standardized in protocol EP28-A3c from the pre-analytical stage onwards. Results: The reference ranges for CD3+, CD4+ and CD8+ were 54.7-81.6% (789-2732 cells/μL), 28.1-57.7% (447-1703 cells/μL) and 15.1-38.8% (226-996 cells/μL), respectively. The CD4+/ CD8+ index was 0.84-3.77. Discussion: The reference values for lymphocyte subpopulations in the healthy Chilean population are different from those currently used in Chile. These observations show local data that could have implications for the treatment of HIV infection and the reference ranges found in this study could be used to understand the local situation of some patients. Conclusions: Others studies must be done to confirm these observations due to lack of previous data and because this is the first study in Chilean population.

Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer.

Anti-angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early-stage (resectable) cancers. Newer investigational anti-angiogenic drugs have been designed to inhibit the Angiopoietin (Ang)-Tie pathway. Acting through Tie2 receptors, the Ang1 ligand is a gatekeeper of endothelial quiescence. Ang2 is a dynamically expressed pro-angiogenic destabilizer of endothelium, and its upregulation is associated with poor prognosis in cancer. Besides using Ang2 blockers as inhibitors of tumor angiogenesis, little attention has been paid to their use as stabilizers of blood vessels to suppress tumor cell extravasation and metastasis. In clinical trials, Ang2 blockers have shown limited efficacy in advanced metastatic disease settings. This review summarizes preclinical evidence suggesting the potential utility of Ang2 inhibitors or Tie2 activators as neoadjuvant or adjuvant therapies in the prevention or treatment of early-stage micrometastatic disease. We further discuss the rationale and potential of combining these strategies with immunotherapy, including immune checkpoint targeting antibodies.

Síndrome de Hamman: una causa rara de dolor torácico en niños / Hamman's syndrome: a rare cause of thoracic pain in children

Resumen Introducción: el dolor torácico es una causa frecuente de consulta al servicio de urgencias pediátricas. Una causa poco conocida es el neumomediastino, el cual puede clasificarse en secundario, cuando hay un desencadenante y en espontáneo, cuando no hay causa evidente. También es llamado síndrome de Hamman, el cual tiene una incidencia que oscila entre uno en 30 000 a 44 000 consultas a urgencias y se presenta predominantemente en hombres. Presentamos el caso de una niña de 12 años, previamente sana, quien consultó por un cuadro de 12 horas de evolución de dolor torácico de características pleuríticas, de inicio súbito, asociado a disnea y diaforesis, sin historia de trauma, síntomas respiratorios, gastrointestinales u otra sintomatología previa. Y a quien posteriormente se le hizo diagnóstico de neumomediastino espontáneo. Discusión: esta enfermedad es muy poco frecuente en niños. La mayoría de los casos se autolimitan rápidamente con manejo sintomático y muy pocos pueden complicarse con taponamiento cardiaco. La radiografía de tórax es el método diagnóstico más preciso.

Abstract Introduction: chest pain is a frequent cause of consultation to the pediatric emergency department. A little-known cause is pneumomediastinum, which can be classified as secondary, when there is a trigger and spontaneous, when there is no evident cause. It is also called Hamman's syndrome, which has an incidence ranging from one in 30 000 to 44 000 emergency department visits and occurs predominantly in males. We present the case of a 12-year-old girl, previously healthy, who consulted for 12 hours of chest pain with pleuritic characteristics of sudden onset, associated with dyspnea and diaphoresis, with no history of trauma, respiratory or gastrointestinal symptoms or other previous symptomatology. The patient was subsequently diagnosed with spontaneous pneumomediastinum. Discussion: this disease is very rare in children. Most cases are rapidly self-limited with symptomatic management and very few can be complicated with cardiac tamponade. Chest radiography is the most accurate diagnostic method.

Local insulin application has a dose-dependent effect on lumbar fusion in a rabbit model.

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.

Cellular birthdate predicts laminar and regional cholinergic projection topography in the forebrain.

The basal forebrain cholinergic system projects broadly throughout the cortex and constitutes a critical source of neuromodulation for arousal and attention. Traditionally, this system was thought to function diffusely. However, recent studies have revealed a high degree of spatiotemporal specificity in cholinergic signaling. How the organization of cholinergic afferents confers this level of precision remains unknown. Here, using intersectional genetic fate mapping, we demonstrate that cholinergic fibers within the mouse cortex exhibit remarkable laminar and regional specificity and that this is organized in accordance with cellular birthdate. Strikingly, birthdated cholinergic projections within the cortex follow an inside-out pattern of innervation. While early born cholinergic populations target deep layers, late born ones innervate superficial laminae. We also find that birthdate predicts cholinergic innervation patterns within the amygdala, hippocampus, and prefrontal cortex. Our work reveals previously unappreciated specificity within the cholinergic system and the developmental logic by which these circuits are assembled.

Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.

Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.

Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer.

The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4+ and CD8+ T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy.