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Abstract Background Respiratory syncytial virus (RSV) is associated with substantial morbidity among infants. This study modelled the potential public health and economic impact of nirsevimab, a long-acting monoclonal antibody, as an immunoprophylactic strategy for all infants in Spain in their first RSV season. Methods A static decision-analytic model of the Spanish birth cohort during its first RSV season was developed to estimate the impact of nirsevimab on RSV-related health events and costs versus the standard of practice (SoP). Spain-specific costs and epidemiological data were used as model inputs. Modelled outcomes included RSV-related outpatient visits, emerging room (ER) visits, hospitalisations – including pediatric intensive care unit (PICU) admission, mechanical ventilation, and inpatient mortality. Results Under the current SoP, RSV caused 151,741 primary care visits, 38,798 ER visits, 12,889 hospitalisations, 1,412 PICU admissions, and 16 deaths over a single season, representing a cost of €71.8 million from a healthcare payer perspective. Universal immunisation of all infants with nirsevimab was expected to prevent 97,157 primary care visits (64.0% reduction), 24,789 ER visits (63.9%), 8,185 hospitalisations (63.5%), 869 PICU admissions (61.5%), and 9 inpatient deaths (52.6%), saving €47.8 million (62.4%) in healthcare costs. Conclusions These results suggest that immunisation with nirsevimab of all infants experiencing their first RSV season in Spain is likely to prevent thousands of RSV-related health events and save considerable costs versus the current SoP.

Abstract Background The World Health Organization’s (WHO) Mental Health Gap Action Programme (mhGAP) aims to provide evidence-based guidelines for the management of mental, neurological, and substance use disorders in non-specialized healthcare settings. However, implementing these guidelines remains a challenge due to various factors, including limited training opportunities for primary care providers. This study con the effectiveness of a social media-delivered distance education program on the mhGAP intervention guide, to overcome barriers of technology access and digital literacy, providing a familiar and accessible platform for primary care providers in Jalisco. Methods A quasi-experimental study with a pre-test/post-test design was conducted. Primary care providers from Jalisco were invited to participate in a distance education program on the mhGAP intervention guide. The program consisted of online modules, webinars, and discussion forums facilitated by mental health experts. Knowledge assessments were conducted before and after the intervention using a standardized questionnaire. Participant satisfaction and perceived utility were also evaluated through surveys and focus group discussions. Results A total of 1,096 primary care providers completed the program. The mean knowledge score significantly improved from 58.2% (SD = 12.8%) in the pre-test to 81.4% (SD = 9.6%) in the post-test (p

Abstract The underlying evolutionary mechanisms driving global expansions of pathogen strains are poorly understood. Vibrio parahaemolyticus is one of only two marine pathogens where variants have emerged in distinct climates globally. The success of a Vibrio parahaemolyticus clone (VpST3) in Latin America- the first spread identified outside its endemic region of tropical Asia- provided an invaluable opportunity to investigate mechanisms of VpST3 expansion into a distinct marine climate. A global collection of VpST3 isolates and novel Latin American isolates were used for evolutionary population genomics, pangenome analysis and combined with oceanic climate data. We found a VpST3 population (LatAm-VpST3) introduced in Latin America well before the emergence of this clone in India, previously considered the onset of the VpST3 epidemic. LatAm-VpST3 underwent successful adaptation to local conditions over its evolutionary divergence from Asian VpST3 isolates, to become dominant in Latin America. Selection signatures were found in genes providing resilience to the distinct marine climate. Core genome mutations and accessory gene presences that promoted survival over long dispersals or increased environmental fitness were associated with environmental conditions. These results provide novel insights into the global expansion of this successful V. parahaemolyticus clone into regions with different climate scenarios.

Abstract Objective Evidence from low- and middle-income countries regarding the effect of smoking in people with diabetes is lacking. Here, we report the association of smoking with mortality in a large cohort of Mexican adults with diabetes. Methods Participants with diabetes mellitus (self-reported diagnosis, use of antidiabetic medications or HbA1c ≥ 6.5%) aged 35–74 years when recruited into the Mexico City Prospective Study were included. Cox regression confounder-adjusted mortality rate ratios (RRs) associated with baseline smoking status were estimated. Results Among 15,975 women and 8225 men aged 35–74 years with diabetes but no other comorbidities at recruitment, 2498 (16%) women and 2875 (35%) men reported former smoking and 2753 (17%) women, and 3796 (46%) men reported current smoking. During a median of 17 years of follow-up there were 5087 deaths at ages 35–74 years. Compared with never smoking, all-cause mortality RR was 1.08 (95%CI 1.01–1.17) for former smoking, 1.11 (95%CI 1.03–1.20) for current smoking, 1.09 (95%CI 0.99–1.20) for non-daily smoking, 1.06 (95%CI 0.96–1.16) for smoking

The current and predominant school of thought in academic publishing, with a correspondingly rigorously implemented set of ethical policies, notes that classic authorship is a purely human endeavor. However, such rigid conceptual restrictions on authorship for artificial intelligence (AI), like large language models (LLMs), may be borne from fear, emerging perhaps from being intellectually threatened by AI/LLMs that might outperform humans. In this paper, considering several caveats, a world of academic publishing in which AI/LLMs are offered a fair opportunity of authorship, coined AI-authorship, is envisioned.

Abstract Background Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body’s cellular response to a hot environment. Objective This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. Methods We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. Results At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (β: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. Conclusions These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

The aim of this article is to elucidate the rational foundations upon which personalist bioethics is built, thereby enhancing understanding regarding its place within the broader discourse of secular bioethics. Personalist bioethics, as a dynamic pursuit, actively engages with scientific discoveries, periodically revisiting them and considering contemporary individualsʼ diverse perceptions of identity and values. It integrates two foundational trunks: personalism and Aristotelian-Thomistic theology with metaphysical reference. The method employed by personalist bioethics is illustrated through triangulation: the exposition of biomedical reality, an in-depth study of anthropological significance, and the identification of values at stake. Rooted in a substantialist concept of the human person, it follows a systematic interaction of various knowledge spheres, aiming not only to describe problematic relations but also to propose prescriptive solutions. Personalism maintains that the human person is valuable for who he is and not only for the choices he makes; he is a source from which the choices proceed. According to personalist ethics, the ethical value of an act will have to be considered under the subjective aspect of intentionality, but it will also have to be considered in terms of its objective content and its consequences. The natural moral law that urges every conscience to do good and avoid evil, therefore, becomes concrete in respect for the human person in all the fullness of his values, his essence, and ontological dignity.

Peru reported the second-highest COVID-19 cases in Latin America, after Brazil. The first COVID-19 wave occurred between March–December 2020, and the second occurred between January–September 2021. The differences between these waves remain largely unknown, and there is no comparison between them in Peru. We evaluated the variation in the clinical and epidemiological components of COVID-19-affected patients in both waves in northern Peru by a retrospective study using the clinical follow-up database of Lambayeque and the epidemiological notification form database of NotiWeb. The COVID-19-associated factors during the two waves were determined using simple and multiple regression analysis, and the prevalence ratio (PR) was estimated. During the second wave of COVID-19, there was an increase in cough symptoms in 12.1%, odynophagia in 5.0%, and chills in 16.0% compared with the first wave. The second wave was marked by a higher proportion of affected adolescents and children and a greater percentage of respiratory symptoms than the first wave.

Abstract Background Emerging zoonotic diseases arise from cross-species transmission events between wild or domesticated animals and humans, with bats being one of the major reservoirs of zoonotic viruses. Viral metagenomics has led to the discovery of many viruses, but efforts have mainly been focused on some areas of the world and on certain viral families. Methods We set out to describe full-length genomes of new picorna-like viruses by collecting feces from hundreds of bats captured in different regions of Spain. Viral sequences were obtained by high-throughput Illumina sequencing and analyzed phylogenetically to classify them in the context of known viruses. Linear discriminant analysis (LDA) was performed to infer likely hosts based on genome composition. Results We found five complete or nearly complete genomes belonging to the family Picornaviridae, including a new species of the subfamily Ensavirinae. LDA suggested that these were true vertebrate viruses, rather than viruses from the bat diet. Some of these viruses were related to picornaviruses previously found in other bat species from distant geographical regions. We also found a calhevirus genome that most likely belongs to a proposed new family within the order Picornavirales, and for which genome composition analysis suggested a plant host. Conclusions Our findings describe new picorna-like viral species and variants circulating in the Iberian Peninsula, illustrate the wide geographical distribution and interspecies transmissibility of picornaviruses, and suggest new hosts for calheviruses.

Abstract The Philippines is a high-incidence country for tuberculosis, with the increasing prevalence of multi- (MDR-TB) and extensively-drug (XDR-TB) resistant Mycobacterium tuberculosis strains posing difficulties to disease control. Understanding the genetic diversity of circulating strains can provide insights into underlying drug resistance mutations and transmission dynamics, thereby assisting the design of diagnostic tools, including those using next generation sequencing (NGS) platforms. By analysing genome sequencing data of 732 isolates from Philippines drug-resistance survey collections spanning from 2011 to 2019, we found that the majority belonged to lineages L1 (531/732; 72.5%) and L4 (European-American; n = 174; 23.8%), with the Manila strain (L1.2.1.2.1) being the most prominent (475/531). Approximately two-thirds of isolates were found to be at least MDR-TB (483/732; 66.0%), and potential XDR-TB genotypic resistance was observed (3/732; 0.4%), highlighting an emerging problem in the country. Genotypic resistance was highly concordant with laboratory drug susceptibility testing. By finding isolates with (near-)identical genomic variation, five major clusters containing a total of 114 isolates were identified: all containing either L1 or L4 isolates with at least MDR-TB resistance and spanning multiple years of collection. Closer inspection of clusters revealed transmission in prisons, some involving isolates with XDR-TB, and mutations linked to third-line drug bedaquiline. We have also identified previously unreported mutations linked to resistance for isoniazid, rifampicin, ethambutol, and fluoroquinolones. Overall, this study provides important insights into the genetic diversity, transmission and circulating drug resistance mutations of M. tuberculosis in the Philippines, thereby informing clinical and surveillance decision-making, which is increasingly using NGS platforms.

Abstract Despite substantial growth in wind energy technology in recent decades, aerodynamic modeling of wind turbines relies on momentum models derived in the late 19th and early 20th centuries, which are well-known to break down under flow regimes in which wind turbines often operate. This gap in theoretical modeling for rotors that are misaligned with the inflow and also for high-thrust rotors has resulted in the development of numerous empirical corrections which are widely applied in textbooks, research articles, and open-source and industry design codes. This work reports a Unified Momentum Model to efficiently predict power production, thrust force, and wake dynamics of rotors under arbitrary inflow angles and thrust coefficients without empirical corrections. The Unified Momentum Model is additionally coupled with a blade element model to enable blade element momentum modeling predictions of wind turbines in high thrust coefficient and yaw misaligned states without using corrections for these states. This Unified Momentum Model can form a new basis for wind turbine modeling, design, and control tools from first principles and may enable further development of innovations necessary for increased wind production and reliability to respond to 21st century climate change challenges.

We report the rediscovery, a century after its last record, of two specimens of Pristimantis ruidus from approximately 6 km northeast of its type locality, in a montane forest from the western Andes of southern Ecuador. This species, described by John D. Lynch in 1979, based on specimens collected in 1922 by George H. Tate, was previously known only from the type series, all specimens originating from a single locality (Molleturo, Provincia Azuay, Ecuador, 2317 m elev.). The rediscovery occurred in November 2022 in the Reserva de Conservación Quitahuaycu, Molleturo Parish, Azuay Province. The two specimens, both females, are characterised by rough skin with numerous rounded low warts and tubercles on their dorsum, a W-shaped occipital fold, tympanum and tympanic ring not externally visible and by the lack of cranial crests, characters that correspond with the description of the holotype. We evaluate the phylogenetic relationships, based on two mitochondrial genes (12S and 16S rRNA) and one nuclear gene (RAG-1). These analyses reveal Pristimantis ruidus as a member of the subgenus Huicundomantis, being most closely related to P. philipi, a species with a distribution restricted to the paramo of the same mountain region (Macizo del Cajas). Pristimantis ruidus co-exists with Pristimantis jimenezi, three additional species of Pristimantis and one Noblella with uncertain taxonomic status. This rediscovery underscores the urgency of implementing effective conservation and monitoring measures for the few remnants of the original ecosystems from western Ecuador, which face ongoing anthropogenic threats and harbour a diversity that remains insufficiently studied.

Abstract Background Critical care management heavily relies on accurate cardiac output (CO) measurement. Echocardiography has been a mainstay in non-invasive cardiac monitoring; however, its comparability to invasive methods warrants further exploration. Recent studies have suggested the potential of carotid Doppler measurements as a promising approach to estimate CO. Despite this potential, the literature presents mixed outcomes regarding its reliability and accuracy. This study aims to evaluate the correlation and concordance between carotid Doppler ultrasonography and invasive hemodynamic monitoring in estimating CO in critically ill patients. Furthermore, it assesses the concordance and correlation between echocardiography CO and the standard invasive CO measurements. Methods This concordance study involved critically ill adults requiring invasive CO measurement. Patients with arrhythmias, severe valvulopathy, pregnancy, and poor acoustic window were excluded. Statistical analyses comprised univariate analysis, Wilcoxon signed-rank test, Spearman correlation, and intraclass correlation coefficient. Ethical approval was granted by the institution’s ethics committee. Results A total of 49 critically ill patients were included, predominantly male (63.27%), with a median age of 57 years. Diagnoses included subarachnoid hemorrhage (53.06%) and heart failure (8.16%). Mean cardiac index was 3.36 ± 0.81 L/min/m2 and mean cardiac output was 5.98 ± 1.47 L/min. Spearman correlation coefficient between echocardiography and invasive CO measurements was 0.58 (p-value = p

Abstract Background Diet and exercise are important components of treatment for complex chronic conditions, however access to allied health support is limited. When available, support is often siloed and fragmented. Digital health incorporating patient choice may help to align health care services with preferences and goals. This study evaluated the implementation of a ubiquitously accessible patient-centred digital health diet and exercise service. Methods U-DECIDE was a single-centre, 26-week randomised controlled trial set in kidney and liver disease clinics in a tertiary hospital in Brisbane, Australia. Participants were adults with a complex chronic condition referred for dietetic consultation with at least one feature of the metabolic syndrome. All participants received a dietary consultation, an activity monitor and usual care. Intervention participants were offered one text message per week and access to additional digital health options (increased text message frequency, nutrition app, exercise app, group-based diet and/or exercise video consultations). The primary outcome of feasibility was determined by safety (study-related serious adverse events: SRSAEs), recruitment (≥ 50% eligible patients), retention (≥ 70%), exposure uptake (≥ 75% of intervention group had greater access to health professional contact than comparator) and video consultation adherence (≥ 80% attendance). Secondary outcomes included process evaluation metrics and clinical outcomes. Results Of 67 participants (intervention n = 33, comparator n = 34), 37 (55%) were men, median (IQR) age was 51 (41–58) years. The most chosen digital health options were the nutrition app (n = 29, 88%) and exercise video consultations (n = 26, 79%). Only one participant chose no additional digital health options. The intervention group had no SRSAEs. The study exceeded targets for recruitment (52%), retention (81%) and exposure uptake (94%). Video consultation adherence was 42%. Engagement across digital health options was inconsistent. Conclusions Digital health options incorporating patient choice were feasible and can be offered to people with complex chronic disease as a service model option. Trial registration Australia and New Zealand Trials Register: Trial Registration Number: ACTRN12620001282976. Registered 27th November 2020.

Abstract Background Congenital Myasthenic Syndromes (CMS) are rare genetic diseases, which share as a common denominator muscle fatigability due to failure of neuromuscular transmission. A distinctive clinical feature of presynaptic CMS variants caused by defects of the synthesis of acetylcholine is the association with life-threatening episodes of apnea. One of these variants is caused by mutations in the SLC5A7 gene, which encodes the sodium-dependent HC-3 high-affinity choline transporter 1 (CHT1). To our knowledge there are no published cases of this CMS type in Latin America. Case presentation We present two cases of CHT1-CMS. Both patients were males presenting with repeated episodes of apnea, hypotonia, weakness, ptosis, mild ophthalmoparesis, and bulbar deficit. The first case also presented one isolated seizure, while the second case showed global developmental delay. Both cases, exhibited incomplete improvement with treatment with pyridostigmine. Conclusions This report emphasizes the broad incidence of CMS with episodic apnea caused by mutations in the SLC5A7 gene and the frequent association of this condition with serious manifestations of central nervous system involvement.

RESUMEN Introducción y objetivos: La mayoría de los pacientes con embolia pulmonar (EP) aguda reciben únicamente anticoagulación. La reperfusión es necesaria en los pacientes con EP de alto riesgo y en una minoría de pacientes con EP de riesgo intermedio-alto. La trombólisis sistémica (TS) es el tratamiento de reperfusión de primera línea, pero debido a las contraindicaciones y a la preocupación por las hemorragias graves, las terapias dirigidas por catéter (TDC) están surgiendo como una alternativa adecuada. El objetivo del presente estudio fue detectar predictores del uso de TDC con respecto a otras terapias en pacientes con EP aguda. Métodos: Este registro incluyó pacientes consecutivos con EP de riesgo intermedio y alto en dos centros terciarios, con un equipo de respuesta a la EP, desde 2014 hasta 2022. Los pacientes se agruparon según la terapia inicial: solo anticoagulación, TDC o TS; y se evaluaron los predictores de selección de terapia y variables de seguridad. Resultados: Se incluyó a un total de 274 pacientes. De ellos, 112 recibieron solo anticoagulación, 96 recibieron TS como tratamiento primario y 66 fueron sometidos a TDC en un primer momento. Las comorbilidades fueron mayores en el grupo TDC que en los otros dos. Los pacientes sometidos a TS o TDC presentaban mayores parámetros de gravedad de la EP al ingreso hospitalario. Tras el análisis multivariable, el índice de comorbilidad de Charlson (OR = 1,29; IC95%, 1,05-1,59), la cirugía reciente (OR = 11,07; IC95%, 3,07-39,87) y la EP central bilateral (OR = 2,42; IC95%, 1,10-5,32) siguieron siendo predictores independientes del uso de TDC. En cuanto a los resultados precoces de seguridad, sólo se produjeron hemorragias intracraneales en el grupo TS (1,8% de los pacientes). Conclusiones: Este registro contemporáneo utilizó TDC como terapia inicial en el 24% de los pacientes de riesgo intermedio y alto, principalmente en pacientes comórbidos y posquirúrgicos. La TDC fue una alternativa segura y eficaz al tratamiento médico en pacientes seleccionados.

ABSTRACT Introduction and objectives: Most patients with acute pulmonary embolism (PE) receive anticoagulation only. Reperfusion is required in high-risk and a minority of intermediate-risk PE patients. Systemic thrombolysis (ST) is the first-line reperfusion therapy, but due to contraindications and major bleeding concerns, the use of catheter-directed therapies (CDT) is increasing as a suitable alternative. The objective of the present study was to detect predictors of the use of CDT compared with other therapies in patients with acute PE. Methods: This registry included consecutive intermediate- and high-risk PE patients in 2 tertiary centers with a 24/7 PE response team from 2014 to 2022. The patients were grouped according to the primary treatment: anticoagulation only, CDT, or ST. We evaluated predictors of treatment assignment and safety endpoints. Results: A total of 274 patients were included. Of them, 112 received anticoagulation only, 96 received ST as the primary treatment, and 66 underwent CDT first. Comorbidities were higher in the CDT group than in the other 2 groups. Patients undergoing ST/CDT had higher PE severity parameters at hospital admission. On multivariable analysis, independent predictors for the use of CDT were Charlson Comorbidity Index (OR, 1.29; 95%CI, 1.05-1.59), recent surgery (OR, 11.07; 95%CI, 3.07-39.87), and bilateral central PE (OR, 2.42; 95%CI, 1.10-5.32). Analysis of early safety outcomes showed that intracranial bleeding occurred only in the ST group (1.8% of patients). Conclusions: This contemporary registry used CDT as the primary treatment in 24% of intermediate- and high-risk patients, mainly in comorbid and postsurgical patients. CDT was a safe and effective alternative to medical therapy in selected patients.

Abstract Background Repetitive Transcranial Magnetic Stimulation (rTMS) and EEG-guided neurofeedback techniques can reduce motor symptoms in Parkinson’s disease (PD). However, the effects of their combination are unknown. Our objective was to determine the immediate and short-term effects on motor and non-motor symptoms, and neurophysiological measures, of rTMS and EEG-guided neurofeedback, alone or combined, compared to no intervention, in people with PD. Methods A randomized, single-blinded controlled trial with 4 arms was conducted. Group A received eight bilateral, high-frequency (10 Hz) rTMS sessions over the Primary Motor Cortices; Group B received eight 30-minute EEG-guided neurofeedback sessions focused on reducing average bilateral alpha and beta bands; Group C received a combination of A and B; Group D did not receive any therapy. The primary outcome measure was the UPDRS-III at post-intervention and two weeks later. Secondary outcomes were functional mobility, limits of stability, depression, health-related quality-of-life and cortical silent periods. Treatment effects were obtained by longitudinal analysis of covariance mixed-effects models. Results Forty people with PD participated (27 males, age = 63 ± 8.26 years, baseline UPDRS-III = 15.63 ± 6.99 points, H&Y = 1–3). Group C showed the largest effect on motor symptoms, health-related quality-of-life and cortical silent periods, followed by Group A and Group B. Negligible differences between Groups A-C and Group D for functional mobility or limits of stability were found. Conclusions The combination of rTMS and EEG-guided neurofeedback diminished overall motor symptoms and increased quality-of-life, but this was not reflected by changes in functional mobility, postural stability or depression levels. Trial registration NCT04017481.

Abstract Public engagement with research (PEwR) has become increasingly integral to research practices. This paper explores the process and outcomes of a collaborative effort to address the ethical implications of PEwR activities and develop tools to navigate them within the context of a University Medical School. The activities this paper reflects on aimed to establish boundaries between research data collection and PEwR activities, support colleagues in identifying the ethical considerations relevant to their planned activities, and build confidence and capacity among staff to conduct PEwR projects. The development process involved the creation of a taxonomy outlining key terms used in PEwR work, a self-assessment tool to evaluate the need for formal ethical review, and a code of conduct for ethical PEwR. These tools were refined through iterative discussions and feedback from stakeholders, resulting in practical guidance for researchers navigating the ethical complexities of PEwR. Additionally, reflective prompts were developed to guide researchers in planning and conducting engagement activities, addressing a crucial aspect often overlooked in formal ethical review processes. The paper reflects on the broader regulatory landscape and the limitations of existing approval and governance processes, and prompts critical reflection on the compatibility of formal approval processes with the ethos of PEwR. Overall, the paper offers insights and practical guidance for researchers and institutions grappling with ethical considerations in PEwR, contributing to the ongoing conversation surrounding responsible research practices.

Chitons are molluscs with scarce world records in estuaries. In the present study, we provide the first records of two species of Polyplacophora in the Coreaú River estuary, Camocim, Ceará, Brazil: Ischnochiton striolatus and Ischnoplax pectinata. The data shows these animals thrive in estuary coastal regions. The taxonomic data together with the ecological data presented in this study, it is possible to conclude that this research represents a significant milestone in understanding the biodiversity of Brazilian estuarine areas.

Abstract Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of IMEs is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices. Over the past few years, the characterization of the neuroinflammatory response has grown in sophistication, with the most recent advances focusing on mRNA expression following IME implantation. While gene expression studies increase our broad understanding of the relationship between IMEs and cortical tissue, advanced proteomic techniques have not been reported. Proteomic evaluation is necessary to describe the diverse changes in protein expression specific to neuroinflammation, neurodegeneration, or tissue and cellular viability, which could lead to the further development of targeted intervention strategies designed to improve IME functionality. In this study, we have characterized the expression of 62 proteins within 180 μm of the IME implant site at 4-, 8-, and 16-weeks post-implantation. We identified potential targets for immunotherapies, as well as key pathways that contribute to neuronal dieback around the IME implant.

Abstract Recent discoveries in biology have highlighted the importance of protein and RNA-based condensates as an alternative to classical membrane-bound organelles. Here, we demonstrate the design of pure RNA condensates from nanostructured, star-shaped RNA motifs. We generate condensates using two different RNA nanostar architectures: multi-stranded nanostars whose binding interactions are programmed via linear overhangs, and single-stranded nanostars whose interactions are programmed via kissing loops. Through systematic sequence design, we demonstrate that both architectures can produce orthogonal (distinct and immiscible) condensates, which can be individually tracked via fluorogenic aptamers. We also show that aptamers make it possible to recruit peptides and proteins to the condensates with high specificity. Successful co-transcriptional formation of condensates from single-stranded nanostars suggests that they may be genetically encoded and produced in living cells. We provide a library of orthogonal RNA condensates that can be modularly customized and offer a route toward creating systems of functional artificial organelles for the task of compartmentalizing molecules and biochemical reactions.

Abstract Background To report the risk of exudation recurrence and long-term outcomes in patients with choroidal neovascularization secondary to angioid streaks, according to its morphology and characteristics by optical coherence tomography angiography. Methods Retrospective analysis of electronic medical records from three hospitals. We enrolled patients with a clinical diagnosis of angioid streaks choroidal neovascularization that had a minimum follow-up of 12 months. From each record, we extracted general demographic data, best corrected visual acuity (baseline, before and after each disease recurrence and last on file), type of treatment, time between last intravitreal injection and disease recurrence, and classification of the neovascular lesion morphology by optical coherence tomography, and optical coherence tomography angiography. Patients with myopic choroidal neovascularization were used as controls. Interobserver agreement was assessed with a Cohen-Kappa test. The Odds ratio was calculated with a chi2 test for significance. Visual acuity change through time was evaluated with an ANOVA for repeated measurements with an alpha value of 0.05 for statistical significance. Results We enrolled 30 patients in the study group and 14 in the control group. In the study group, the baseline and final BCVA were 0.861 ± 0.59 and 1.095 ± 0.61 logMAR (p = 0.1) respectively. Control group: 1.045 ± 0.57 and 0.617 ± 0.53 logMAR (p

Abstract Background Firearm homicide and opioid overdoses were already leading causes of death in the U.S. before both problems surged during the COVID-19 pandemic. Firearm violence, overdoses, and COVID-19 have all disproportionately harmed communities that are socially and economically marginalized, but the co-occurrence of these problems in the same communities has received little attention. To describe the co-occurrence of firearm homicides and opioid overdose deaths with COVID-19 mortality we used 2017–2021 medical examiner’s data from Chicago, IL. Deaths were assigned to zip codes based on decedents’ residence. We stratified zip codes into quartiles by COVID-19 mortality rate, then compared firearm homicide and fatal opioid overdose rates by COVID-19 quartile. Findings Throughout the study period, firearm homicide and opioid overdose rates were highest in the highest COVID-19 mortality quartile and lowest in the lowest COVID-19 mortality quartile. Increases in firearm homicide and opioid overdose were observed across all COVID-19 mortality quartiles. Conclusions High co-occurrence of these deaths at the community level call for addressing the systemic forces which made them most vulnerable before the pandemic. Such strategies should consider the environments where people reside, not only where fatal injuries occur.

Abstract Background Quality of life (QoL) is an important determinant of physical and mental health. QoL in head and neck cancer tends to deteriorate due to changes in the physical, functional, psychological aspects. EORTC-QLQ-H&N35 is an instrument that measure the QoL specifically in head and neck cancer patients. EORTC-QLQ-H&N35 give a numeric value to QoL of patients with high value correspond to better QoL. Objective The aim of present study was to find out the cut-off points of numeric values of EORTC-QLQ-H&N35 to categorize QoL impairment into different categories (normal, mild, moderate, and severe). Present study also aims analyze the QoL among head and neck cancer patients under these new categories. Methodology Total 205 patients of head and neck cancer visiting to the outpatient unit were enrolled in this study. Hindi version of EORTC-QLQ-H&N35 was used to evaluate the QoL. Total 9 classification schemes were created with different cut-off points to classify the global QoL score into normal, mild, moderate and severe categories. QoL data was then analyze using the scheme having highest F value in ANOVA test. Results Classification scheme having cut-off values 76–100 for normal QoL, 51–75 for mild QoL impairment, 26–50 for moderate and 0–25 for severe QoL impairment found to have highest F value (729.915) in ANOVA test. The mean QoL score among total 205 patients were 60.08 ± 19.06. Based on the new classification scheme, QoL was normal in 46 (22.4%) patients whereas QoL was impaired to mild level in 76 (37.1%) patients, to moderate level in 76 (37.1%) and to severe level in 7 (3.4%) patients. Role functioning, emotional functioning and social functioning was impaired to severe level in 4 (2.0%), 13 (6.3%) and 3 (1.5%) patients respectively. Conclusion EORTC-QLQ-H&N35 offer a comprehensive review of QoL in head and neck cancer patients. By designating the QoL score into different categories, it will become easier for clinician to have a better idea of QoL of head and neck cancer patients.

A systematic review of Threshold Concepts provides a thorough and structured analysis of the existing literature related to these essential and transforming concepts in education. Threshold Concepts represent ideas or knowledge that, once understood, allow the student to access deeper levels of understanding of a discipline. These concepts are crucial, since they act as “doors” that, once “crossed”, lead to a more integrated and coherent vision of a study area. In the review, various academic databases were consulted to identify relevant studies, applying rigorous inclusion and exclusion criteria. Through this process, key patterns, methodologies, and findings were detected, related to the teaching, understanding and application of these concepts. Despite the broad methodological diversity that exists in the field, as well as educational approaches and contexts, Threshold Concepts are not always addressed successfully at the curricular level or in the implementation of teaching methodologies. The limitations of this review have an impact on possible publishing bias and the diversity of research methods. However, the review stresses the need for greater integration of these concepts in education, as well as future research that explores efficient pedagogical strategies to teach them.

Abstract To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children’s Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Introduction Dengue disease represents a large and growing global threat to public health, accounting for a significant burden to health systems of endemic countries. The World Health Organization’s (WHO) Strategic Advisory Group of Experts (SAGE) and the European Medicines Agency (EMA) currently recommend the use of TAK-003 dengue vaccine in high dengue burden and transmission settings for countries considering vaccination as part of their integrated management strategy for prevention and control of Dengue.Areas covered This paper describes the main conclusions of a workshop held by the Arbovirus Committee of the Latin American Society of Pediatric Infectious Diseases (SLIPE) in November 2023, to generate consensus recommendations on the introduction of this new vaccine in the region. Considerations were made regarding the molecular epidemiology of dengue infection in the Americas and the need for more precise phylogenetic classification and correlation with clinical outcome and disease severity.Expert opinion Introduction of dengue vaccine should be considered as an strategy for health entities in the region, with participation of social sectors, scientific societies, and ministries of health that could be able to create a successful vaccination program.

Purpose: To summarize the results of Chile's 2022 Report Card (RC) on physical activity (PA) for Children and Adolescents. Methods: Chile's 2022 RC included ten core PA indicators common to the Global Matrix 4.0. Evidence from scientific articles, reports, and databases published between 2018 and January 2022 was included for each indicator. The data were collected and analyzed by a national scientific committee, which assigned letter grades (A to F) using a consensus based on benchmarks defined and revised by the Active Healthy Kids Global Alliance. Results: The committee assigned the following grades: Overall PA, D−; Organized Sports and Physical Activity Participation, C−; Active Play, Incomplete; Active Transportation, D; Sedentary Behavior, D−; Physical Fitness, Incomplete; Family and Peers, D; School, C; Community and Environment, D+; Government, A−. Conclusions: Chile's 2022 RC, like its previous versions, shows persistently low grades for most indicators. Overall PA remained nearly unchanged, while Community and Environment scored lower. Slight improvements were seen in Organized Sports, Family and Peers, and School Environment. While Chile has endeavored to increase children's activity levels, policies require implementation through a systemic, coherent framework to promote sustainable changes and reach a larger portion of children and youth.

The article addresses the diagnostic value of the combined use of computed tomography (CT) perfusion and dual-energy CT (DECT) in patients with neuroendocrine tumors. It emphasizes the heterogeneity and complexity of these neoplasms, primarily affecting the gastrointestinal tract, bronchopulmonary system, and pancreas. While conventional CT is widely employed in their diagnosis, the combination of CT perfusion and dual-energy CT offers greater precision, particularly in detecting synchronous tumors and characterizing their vascularization. A clinical case of a patient with chronic abdominal symptoms, whose diagnosis was facilitated using both combined techniques, is presented. The discussion explores how CT perfusion assesses tumor vascularization and how dual-energy CT improves soft tissue differentiation, resulting in increased diagnostic accuracy. It is highlighted that this approach not only enhances detection rates but also positively impacts clinical management and healthcare costs. Therefore, the importance of considering these advanced tools in the diagnosis of neuroendocrine tumors to improve diagnostic precision and efficiency in patient care is underscored.

Introducción. Colombia alberga dos millones de indígenas, que viven en condiciones de pobreza y tienen deficiencias en salud, por lo cual están expuestos a contraer infecciones virales como la hepatitis B. El departamento del Amazonas presenta una gran prevalencia del virus y barreras para acceder a la vacunación; por esto, parte de la población es propensa a la infección. Objetivo. Identificar factores asociados con la infección por el virus de la hepatitis B en indígenas colombianos. Materiales y métodos. Se llevó a cabo un estudio de casos y controles en mayores de 18 años de cuatro departamentos del país. Los casos se identificaron mediante el registro nacional de notificación de hepatitis B (2015-2022). Los controles seleccionados de manera concurrente fueron pareados con los casos por edad, sexo, etnia y departamento. En una encuesta se consignaron las características sociodemográficas, los factores asociados con el contacto con sangre y fluidos, las prácticas socioculturales y los antecedentes de vacunación. El proyecto fue aprobado por Comité de Ética de la Universidad de Antioquia. Resultados. Participaron 75 casos y 150 controles de 13 grupos étnicos. El departamento del Amazonas aportó el 49 % de los participantes (83 % mujeres) con una mediana de edad de 30 años (RIC = 27-37). Los factores asociados con una mayor probabilidad de contraer la infección fueron el antecedente de algún familiar infectado con el virus de la hepatitis B (OR ajustado = 2,61) (IC95%: 1,09-6,27) y número de embarazos en mujeres, (OR ajustado = 1,61) (IC95%: 1,02-2,54). La vacunación mostró un efecto protector sin asociación significativa. Conclusión. Los aspectos asociados con la convivencia familiar y el número de embarazos contribuyen a una potencial transmisión vertical y horizontal del virus. No se identificaron prácticas culturales asociadas. Se requieren estrategias novedosas y diferenciales para reducir la transmisión del virus de la hepatitis B en poblaciones indígenas.

Recent empirical research in policy design has shown the relevance of micro-level components, particularly specification and calibration, in shaping policy outcomes. Additionally, research highlights the importance that understanding the mechanisms underlying the policy process has for effective policy design. Yet, a gap persists in how to effectively calibrate and specify policies for specific cases, with a theoretical grounding and guidance for practitioners. This paper addresses this need by applying a process theory of change to delineate the key episodes that constitute the mechanisms of a plausible pathway for an effective Program for Ecosystem Services (PES), an incentives-based instrument focused on conserving forests producing carbon sequestration, biodiversity protection, and water infiltration, among other services. Specifically, the paper uses the well-documented Mexican PES to illustrate how to derive the mechanisms and use them for calibration and specification. The paper provides valuable theoretical insights drawn from the case study, contributing to the field of micro-policy design with a mechanistic approach.

Several medium chain fatty acids and different chemical forms of these acids were evaluated in vitro as treatments of aerobically-exposed corn silage against spoilage and pathogenic microbes and for effects on rumen fermentation. Treatments were control (no additive), myristate (MY), laurate (LA), monolaurin (MLA), methyl ester laurate (MELA), a blend of mono-, di- and triglycerides of laurate (BLA), and monocaprylate (MC). After 24 h of aerobic incubation (37°C), yeast and mold growth were not influenced (P > 0.05) by treatments, while the net growth of lactic acid bacteria was decreased, albeit slightly, compared to that by untreated controls (P < 0.01) by all treatments of the air-exposed corn silage. Compared with controls, wild-type enterococci were decreased (P < 0.01) in MLA, MELA, and BLA. Staphylococcus aureus was reduced (P < 0.01) with MLA, MELA, BLA, and MC. Total aerobes showed reductions (P < 0.01) with MLA, BLA, and MC. Listeria monocytogenes numbers were reduced (P < 0.01) with MELA. Anaerobic incubation (24 h; 39°C) of ruminal fluid (10 mL) with 0.2 g air-exposed and MCFA-treated corn silage revealed higher hydrogen accumulations (P < 0.01) with MLA and MC over the control treatment. Methane was decreased (P < 0.01) solely by MLA. There was an increase (P < 0.01) of acetate with MELA and MC; of propionate with MELA or by BLA; and of butyrate with MLA, MELA, BLA, and MC. Total VFA, hexose fermented, and ammonia were increased (P < 0.01) with MELA, BLA, and MC. The acetate:propionate ratio was increased (P < 0.01) with MC. The results showed that treatment of air-exposed corn silage with esterified MCFA had no effect on yeasts and molds but prevented propagation or reduced populations of some unwanted and potentially desirable bacteria. Modest methane reduction was seen during in vitro incubation of rumen fluid suspensions with MLA-treated silage and ammonia accumulations were increased in esterified MCFA-treated silage. Little, if any, other detrimental effects on beneficial ruminal fermentation characteristics were observed.

Objective Little is known about the children of parents who experience homelessness. The At Home/Chez Soi (AHCS) Research Demonstration Project, launched in 2009, was a Canadian multi-site, multi-year study that tested the effectiveness of Housing First. In Winnipeg, 513 people were enrolled, of whom 47% were parents. Our objective was to determine how the children were faring with respect to their health and social situations at a time their parent was experiencing homelessness. Approach The cohort, created using the Manitoba Centre for Health Policy’s familial linkage methodology, consisted of 405 individuals (< 30 years old) who were the offspring of the Winnipeg AHCS cohort. We descriptively summarized the socioeconomic characteristics and indicators of their involvement (or lack thereof) in various government systems at or in a period up to their parent’s study enrolment date. Results Approximately half of the cohort were female (51%) and under 13 years (52%). Most (76%) resided in a household that had received income assistance. At least 50% had been placed into care at or near birth and only 17% had not been involved with the child welfare system. Of those school aged, 81% were enrolled in school and of those older than school aged, 53% had graduated. Nearly half (49%) had been diagnosed with a mental health disorder and/or with asthma (47%). Conclusions and Implications This study is the first in a series seeking to identify ways to prevent multigenerational experiences of homelessness. Findings will generate valuable insights for upstream intervention across various systems.

Background: Species hybridization represents a real concern in terms of parasite transmission, epidemiology and morbidity of schistosomiasis. It is greatly important to better understand the impact of species hybridization for the clinical management. Methods: A prospective observational study was carried out in sub-Saharan migrants who were diagnosed with confirmed genitourinary schistosomiasis. A tailored protocol was applied, including Schistosoma serology, a specific urine LAMP tests for schistosomiasis and an ultrasound examination before treatment with praziquantel. A scheduled follow-up was performed at 3, 6 and 12 months to monitor treatment response, comparing patients carriers of Schistosoma hybrids with carriers of only genetically pure forms. Results: A total of 31 male patients from West Africa were included in the study with a mean age of 26.5 years. Twelve (38.7 %) of the patients were carriers of Schistosoma hybrids. As compared with patients infected with S. haematobium alone, hybrid carriers had lower haemoglobin levels (13.8 g/dL [SD 1.8] vs 14.8 g/dL [SD 1.4], p = 0.04), a greater frequency of hematuria (100 % vs 52.6 %, p = 0.005), a higher ultrasound score (2.64, SD 2.20 vs 0.89, SD 0.99; p = 0.02). However, the presence of hybrids did not result in differences in clinical and analytical responses after treatment. Conclusions: The presence of Schistosoma hybrids seems to cause increased morbidity in infected individuals. However, it does not appear to result in differences in diagnostic tests or in clinical and analytical responses after treatment.

Background: Ustekinumab (UST) is an effective treatment option in Crohn’s disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. Objectives: The aim of our study was to analyze the relationship between UST through levels (UST TL ) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. Design: We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. Methods: The following variables were analyzed at the initiation of UST and at each UST TL measurement: clinical response and remission using the Harvey–Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of UST TL ) and P2 (time between UST TL1 and the second determination of UST TL ). Results: We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median UST TL1 was 3.1 μg/mL (1.6–5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with UST TL1 significantly higher than those who did not achieve remission (3.7 μg/mL (2.3–5.4) vs 2.3 μg/mL (1.1–5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); UST TL (7.2 μg/mL (4.7–11.7) vs 3.4 μg/mL (1.9–6.4); p

RhizoBindingSites is a de novo depurified database of conserved DNA motifs potentially involved in the transcriptional regulation of the Rhizobium , Sinorhizobium , Bradyrhizobium , Azorhizobium , and Mesorhizobium genera covering 9 representative symbiotic species, deduced from the upstream regulatory sequences of orthologous genes (O-matrices) from the Rhizobiales taxon. The sites collected with O-matrices per gene per genome from RhizoBindingSites were used to deduce matrices using the dyad-Regulatory Sequence Analysis Tool (RSAT) method, giving rise to novel S-matrices for the construction of the RizoBindingSites v2.0 database. A comparison of the S-matrix logos showed a greater frequency and/or re-definition of specific-position nucleotides found in the O-matrices. Moreover, S-matrices were better at detecting genes in the genome, and there was a more significant number of transcription factors (TFs) in the vicinity than O-matrices, corresponding to a more significant genomic coverage for S-matrices. O-matrices of 3187 TFs and S-matrices of 2754 TFs from 9 species were deposited in RhizoBindingSites and RhizoBindingSites v2.0, respectively. The homology between the matrices of TFs from a genome showed inter-regulation between the clustered TFs. In addition, matrices of AraC, ArsR, GntR, and LysR ortholog TFs showed different motifs, suggesting distinct regulation. Benchmarking showed 72%, 68%, and 81% of common genes per regulon for O-matrices and approximately 14% less common genes with S-matrices of Rhizobium etli CFN42, Rhizobium leguminosarum bv. viciae 3841, and Sinorhizobium meliloti 1021. These data were deposited in RhizoBindingSites and the RhizoBindingSites v2.0 database ( http://rhizobindingsites.ccg.unam.mx /).

We present a novel neural network-based method for analyzing intra-voxel structures, addressing critical challenges in diffusion-weighted MRI analysis for brain connectivity and development studies. The network architecture, called the Local Neighborhood Neural Network, is designed to use the spatial correlations of neighboring voxels for an enhanced inference while reducing parameter overhead. Our model exploits these relationships to improve the analysis of complex structures and noisy data environments. We adopt a self-supervised approach to address the lack of ground truth data, generating signals of voxel neighborhoods to integrate the training set. This eliminates the need for manual annotations and facilitates training under realistic conditions. Comparative analyses show that our method outperforms the constrained spherical deconvolution (CSD) method in quantitative and qualitative validations. Using phantom images that mimic in vivo data, our approach improves angular error, volume fraction estimation accuracy, and success rate. Furthermore, a qualitative comparison of the results in actual data shows a better spatial consistency of the proposed method in areas of real brain images. This approach demonstrates enhanced intra-voxel structure analysis capabilities and holds promise for broader application in various imaging scenarios.

There are few validated contextual measures predicting adoption of evidence-based programs. Variation in context at clinical sites can hamper dissemination. We examined organizational characteristics of Veterans Affairs hospitals implementing STRIDE, a hospital walking program, and characteristics’ influences on program adoption. Using a parallel mixed-method design, we describe context and organizational characteristics by program adoption. Organizational characteristics included: organizational resilience, implementation climate, organizational readiness to implement change, highest complexity sites versus others, material support, adjusted length of stay (LOS) above versus below national median, and improvement experience. We collected intake forms at hospital launch and qualitative interviews with staff members at 4 hospitals that met the initial adoption benchmark, defined as completing supervised walks with 5+ unique hospitalized Veterans during months 5 to 6 after launch with low touch implementation support. We identified that 31% (n = 11 of 35) of hospitals met adoption benchmarks. Seven percent of highest complexity hospitals adopted compared to 48% with lower complexity. Forty-three percent that received resources adopted compared to 29% without resources. Thirty-six percent of hospitals with above-median LOS adopted compared to 23% with below-median. Thirty-five percent with at least some implementation experience adopted compared to 0% with very little to no experience. Adopters reported higher organizational resilience than non-adopters (mean = 23.5 [SD = 2.6] vs 22.7 [SD = 2.6]). Adopting hospitals reported greater organizational readiness to change than those that did not (mean = 4.2 [SD = 0.5] vs 3.8 [SD = 0.6]). Qualitatively, all sites reported that staff were committed to implementing STRIDE. Participants reported additional barriers to adoption including challenges with staffing and delays associated with hiring staff. Adopters reported that having adequate staff facilitated implementation. Implementation climate did not have an association with meeting STRIDE program adoption benchmarks in this study. Contextual factors which may be simple to assess, such as resource availability, may influence adoption of new programs without intensive implementation support.

In today’s information age, recommender systems have become an essential tool to filter and personalize the massive data flow to users. However, these systems’ increasing complexity and opaque nature have raised concerns about transparency and user trust. Lack of explainability in recommendations can lead to ill-informed decisions and decreased confidence in these advanced systems. Our study addresses this problem by integrating explainability techniques into recommendation systems to improve both the precision of the recommendations and their transparency. We implemented and evaluated recommendation models on the MovieLens and Amazon datasets, applying explainability methods like LIME and SHAP to disentangle the model decisions. The results indicated significant improvements in the precision of the recommendations, with a notable increase in the user’s ability to understand and trust the suggestions provided by the system. For example, we saw a 3% increase in recommendation precision when incorporating these explainability techniques, demonstrating their added value in performance and improving the user experience.

Objective: The role of β-hCG in breast cancer is largely unknown, this study aims to analyse the gene expression and clinical implications of β-hCG and its isoforms in various cancers focussing particularly in Breast Invasive Carcinoma (BRCA). A mechanistic approach deciphering the transcriptional regulation of β-hCG by BRCA1 was also explored. Methods: Data from various comprehensive gene expression platforms like UALCAN, GEPIA2, GENT2, TIMER2, LinkedOmics, and STRING were used to analyse the expression of β-hCG and its clinical implications; Immunohistochemistry and ELISA for β-hCG expression analysis from human breast cancer patients; Electrophoretic mobility shift assay (EMSA) to analyse the direct binding of BRCA1 on β-hCG; Immunoblotting and Luciferase assay to understand the regulation of β-hCG by p53 were performed. Results: Results from UALCAN and GENT2 gene expression cancer database revealed that TNBC subtypes and high-grade metaplastic carcinoma shows elevated expression of β-hCG and infiltration of various immune cells were also identified in BRCA by TIMER2. It was observed that most of the isoforms of β-hCG (CGB) are upregulated in breast cancers irrespective of hormonal status when BRCA1 gene is mutated according to TIMER2. Similar results were observed with Lymphoid neoplasm diffuse large B-cell lymphoma (LGG) and DLBC (Brain lower grade glioma) when BRCA1 is mutated. These results correlate with our earlier reports indicating expression of β-hCG in BRCA1 defective condition. We have also identified direct binding of BRCA1 on β-hCG promoter. Conclusion: All these findings demonstrate the importance of β-hCG as a potential target in BRCA1-deficient carcinomas.

IntroductionEnrolling children with cancer in early phase trials is crucial to access innovative treatments, contributing to advancing pediatric oncology research and providing tailored therapeutic options. Our objective is to analyze the impact of these trials on patient outcomes and safety, and to examine the evolution and feasibility of trials in pediatric cancer over the past decade.MethodsAll patients recruited in pediatric anticancer phase I/II clinical trials from January 2014 to December 2022 were included. Clinical records and trial protocols were analyzed.ResultsA total of 215 patients (median age 11.2 years, range 1–29.5) were included in 52 trials (258 inclusions). Patients with extracranial solid tumors (67%), central nervous system (CNS) tumors (24%), and leukemia (9%) were included. The most common investigational drugs were small molecules (28.3%) and antibodies (20.5%). Serious adverse events were experienced by 41% of patients, 4.4% discontinued treatment because of toxicity and two had toxic deaths. Median event-free survival was 3.7 months (95%CI: 2.8–4.5), longer in phase II trials than in phase I (2 vs. 6.3 months; p ≤ 0.001). Median overall survival was 12 months (95%CI: 9–15), higher in target-specific vs. non-target-specific trials (14 vs. 6 months; p ≤ 0.001).DiscussionA significant and increasing number of patients have been included in early clinical trials, suggesting that both oncologists and families consider it valuable to be referred to specialized Units to access new therapies. Moreover, our data suggests that participation in early clinical trials, although not without potential toxicities, might have a positive impact on individual outcomes.

En las últimas décadas, los programas de medicina han venido reconociendo e implementando estrategias didácticas orientadas a favorecer un aprendizaje crítico, significativo y abierto. Dentro de ellas, el Aprendizaje Basado en Problemas (ABP) se presenta como una estrategia innovadora con sentido crítico y de autoformación. Por tanto, este estudio busca comprender los aportes de la estrategia didáctica ABP al logro del aprendizaje significativo en estudiantes del programa de medicina de la Universidad de Pamplona. Se opta por un diseño de investigación cualitativo que sigue el proceso hermenéutico para comprender e interpretar las experiencias de las audiencias en torno al uso del ABP, las cuales se abordaron a través de entrevistas semiestructuradas a miembros del Comité de Currículo, encuestas a los profesores mediante un formulario electrónico, y grupos focales con estudiantes. Los datos se analizaron, compararon e interpretaron a la luz de los referentes bibliográficos y los resultados del análisis documental del proyecto educativo del programa (PEP). Se evidencia que hay diferencia entre la orientación del PEP y la propuesta formativa que los profesores llevan al aula, especialmente en lo relacionado con el uso de estrategias didácticas, predominando las tradicionales como la clase magistral. Se identifica un menor uso de estrategias activas, dentro de las que destacan el ABP y el caso clínico, que en ocasiones se confunden debido a su carácter problematizador. El ABP es usado principalmente por profesores que cuentan con formación especializada en pedagogía, pero aún falta mayor estructuración del procedimiento. La motivación se configura como el principal aporte del ABP al logro de aprendizajes significativos

Summary: Background: Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called ‘mB Box-97’. Methods: We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration. Findings: mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model. Interpretation: Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections. Funding: This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.

Soil salinity, a major environmental stress, restricts agricultural production worldwide. Gynura divaricata (L.) DC. is widely cultivated on tropical islands in China and has both edible and medicinal value. NaCl stress and growth indicators, antioxidant enzyme activity, as well as MDA, proline, and soluble sugar content, were determined. Based on the transcriptomic data of tissue-cultured G. divaricata plantlets grown in control (0 mM NaCl) and salt stress (50 and 200 mM NaCl) conditions, gene expression patterns were examined. KEGG enrichment analysis of differentially expressed genes indicated significant enrichment of plant hormone signaling, MAPK signaling, and starch and sucrose metabolism pathways. These findings allowed key biological pathways and salt stress-responsive genes to be identified, thus providing a molecular basis for breeding salt-tolerant G. divaricata varieties. This transcriptomic analysis revealed a complex tolerance mechanism of G. divaricata in response to NaCl, laying a foundation for screening and cloning key genes related to NaCl tolerance and studying their interactions. These findings would allow the molecular basis of NaCl tolerance to be explored, with the aim of breeding NaCl-tolerant varieties.