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Eva Raphael,1,2 Lorenzo Argante,3 Elisa Cinconze,3 Sara Nannizzi,3 Cheyenne Belmont,1 Claire F Mastrangelo,4 Yuan Hu Allegretti,5 Michele Pellegrini,3 Johannes E Schmidt3 1Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA; 2Department of Family and Community Medicine, University of California, San Francisco, CA, USA; 3Clinical Research and Development Center, GSK, Siena, Italy; 4Division of Infectious Diseases and Vaccinology, School of Public Health - University of California, Berkeley, CA, USA; 5Division of Epidemiology, School of Public Health - University of California, Berkeley, CA, USACorrespondence: Johannes E Schmidt, GSK, Clinical Research and Development Center, Via Fiorentina, 1, 53100, Siena, Italy, Tel +393487052179, Email johannes.e.schmidt@gsk.comPurpose: Urinary tract infections (UTIs) are among the most common bacterial infections, with uropathogenic Escherichia coli (UPEC) as the main etiologic agent of uncomplicated UTIs (uUTIs). The prevalence of uUTis caused by organisms with antimicrobial resistance (AMR) is increasing worldwide, complexifying the disease management and increasing the risk of complications. In efforts to develop new strategies for uUTI prevention, it is imperative to understand factors associated with the occurrence of new episodes.Patients and Methods: This retrospective cohort study aimed to assess the incidence of uUTIs caused by UPEC (UPEC-uUTIs) or unknown etiology (untested uUTIs) in adults aged ≥ 18 years receiving care in a San Francisco healthcare system.Results: During 2014– 2019, 1087 UPEC-uUTI and 4106 untested uUTI cases were documented, of which 324 (29.8%; 95% confidence interval: 27.1%– 32.6%) and 1030 (25.1%; 95% confidence interval: 23.8%– 26.4%) were followed by ≥ 1 new episode of uUTI within 12 months. In the UPEC-uUTI cohort, male gender, diagnosis of diabetes mellitus, and prior uUTI were risk factors for new episodes of uUTI. At the time of first UPEC-uUTI diagnosis, antimicrobial prescriptions were retrieved for 41.1% of cases. When tested, AMR was most frequently reported for trimethoprim/sulfamethoxazole or trimethoprim/sulfamethoxazole prescribed with other antimicrobials.Conclusion: Our study provides important information on the incidence and risk of repeated episodes of uUTIs, as well as on AMR related to them. Keywords: uncomplicated urinary tract infection, urinary tract infection risk factors, antimicrobial resistance, urinary tract infection prevention

Abstract Background The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series. Methods We included all RPD patients with a disease duration

Abstract Glioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies. Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation. In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons. This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma.

ABSTRACT: Typically, Swiss-type cheese is made from cow milk. However, in the present work an attempt to expand the sheep supply chain and product offering in this field was made by developing a new type of cheese using Swiss-type cheese technology. The cheese was manufactured under industrial conditions, and fermentations were carried out using freeze-dried commercial starters that are traditionally used in the production of Swiss cheese. Two experimental “Ewiss cheese” (EC) products were produced using raw milk (RM) and pasteurized milk (PM), respectively. Fourteen microbial groups were investigated by plate counts from curd until ripened cheeses. According to microbiological analyses, no statistically significant differences were found between the 2 productions with respect to the group of lactic acid bacteria (LAB). The curds were mainly characterized by mesophilic LAB cocci (7.45 log10 cfu/g in RM-EC and 7.33 log10 cfu/g in PM-EC). However, at the end of the ripening period (9 mo), the cheeses exhibited a higher presence of mesophilic LAB rods. Undesired microbiological groups were found only in the curd of raw milk cheese in the range of 104 to 105 cfu/g, but they were reaching undetectable levels by plate count in the cheese at the end of ripening. The RM-EC and PM-EC were characterized by 76% and 68% of DM, respectively. These cheeses contained 29.30% and 34.36% of protein, and 51.31% and 50.38% of fat, respectively. Textural analysis showed differences in terms of hardness, chewiness, and gumminess between the experimental cheeses and Swiss cheese sold on the market. These differences could be attributed to the higher protein content of ewe milk. The main fatty acids in the cheeses were palmitic acid, myristic acid, oleic acid, and capric acid. Among the organic acids, RM-EC had higher concentrations of lactic acid, whereas PM-EC was higher in propionic acid. The ewe cheeses emitted 46 volatile compounds, including acids, aldehydes, ketones, esters, alcohols, and other compounds. The PM-EC was characterized by the main compounds of Swiss-type cheese: acetic acid, butyric acid, ethyl butyrate, ethyl caproate, propanoic acid, and tetramethylpyrazine. Sensory evaluation showed that the new dairy products were generally appreciated, and PM-EC was the most preferred by the judges. This research has enabled the development of new ewe milk products, which could stimulate the valorization of a sector that has been long neglected and still has a large margin of improvement.

The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.

The emergency of the COVID-19 pandemic spreading in different waves marked an unprecedented world crisis considered as the most critical one since the Second World War. To contain the pandemic spread, governments implemented both prevention measures to limit the occurrence of undesired events and protective measures to reduce the severity of potential consequences, e.g. physical distancing, travel restrictions, working remotely, wearing face masks and prolonged closures of schools and non-essential businesses industries. Consequently, there were substantial economic setbacks and operational disruptions, reduced logistical and productivity performances, in addition to evident health and social impacts. To learn remarkable lessons from COVID-19 experience, this work analysed results of an ad hoc questionnaire to collect workers’ perceptions and to evaluate systems vulnerability and response ability of ensuring business continuity. The data obtained from questionnaires and accident records were processed by a multi-step methodology, to attain descriptive and inferential statistical analyses and identify statistically significant relationships on accident dynamics. Outcome of the study can help improving organizational resilience of systems, referring to its ability to monitor, respond, anticipate and learn, to achieve improved safety levels and support operational continuity, under possible future unexpected events.

The problem of copper (Cu) intoxication and deficiency continues to impact economic gains and animal welfare in sheep husbandry. This study investigated the ovine genome for regions and potential genes under selection for Cu accretion between sheep breeds. For this, we compared ovine single nucleotide polymorphism (SNP) data of three Cu-susceptible breeds with three Cu-tolerant breeds. After merging SNP data of breeds and removal of related individuals, a total of 229 sheep and 45 640 autosomal SNPs were left. Then, we selected 14 individuals per breed into two datasets (datasets 1 and 2) for analysis of selection signatures using the Fixation index, cross-population extended haplotype homozygosity and haplotype-based FLK methods. Selection regions shared by both datasets detected by at least two methods revealed regions on OAR 4, 8 and 11 containing 54 candidate genes under selection for Cu accretion. Enrichment analysis revealed that 19 gene ontologies and 1 enriched Kyoto encyclopaedia of genes and genomes pathway terms were associated with the candidate genes under selection. Genes such as TP53, TNFSF13, TNFSF12, ALOX15, ALOX12, EIF5A and PREP are associated with the regulation of Cu homeostasis, programmed cell death or inflammatory response. We also found an enrichment of arachidonate 15-lipoxygenase activity, arachidonate 12-lipoxygenase activity and ferroptosis that influence cellular inflammation and cell death. These results shed light on ovine genomic regions under selection for Cu accretion and provide information on candidate genes for further studies on breed differences in ovine Cu accretion.

There is limited evidence on the outcomes and safety of mechanical thrombectomy (MT) among patients with acute ischemic stroke (AIS) in the context of cardiac diseases. Our study reviews MT in AIS within the context of cardiac diseases, aiming to identify existing and emerging needs and gaps. PubMed and Scopus were searched until December 31, 2023, using a combination of cardiological diseases and “mechanical thrombectomy” or “endovascular treatment” as keywords. Study design included case reports/series, observational studies, randomized clinical trials, and meta‐analyses/systematic reviews. We identified 943 articles, of which 130 were included in the review. Results were categorized according to the cardiac conditions. MT shows significant benefits in patients with atrial fibrillation (n=139) but lacks data for stroke occurring after percutaneous coronary intervention (n=2) or transcatheter aortic valve implantation (n=5). MT is beneficial in AIS attributable to infective endocarditis (n=34), although functional benefit may be limited. Controversy surrounds the functional outcomes and mortality of patients with AIS with heart failure undergoing MT (n=11). Despite technical challenges, MT appears feasible in aortic dissection cases (n=4), and in patients with left ventricular assist device or total artificial heart (n=10). Data on AIS attributable to congenital heart disease (n=4) primarily focus on pediatric cases requiring technical modifications. Treatment outcomes of MT in patients with cardiac tumors (n=8) vary because of clot consistency differences. After cardiac surgery stroke, MT may improve outcomes with early intervention (n=13). Available data outline the feasibility of MT in patients with AIS attributable to large‐vessel occlusion in the context of cardiac diseases.

Resumen Este artículo es un ejercicio de reflexividad sobre investigaciones etnográficas propias de la infección por SARS-CoV-2 realizadas en 2020-2021. Se analizan aquí experiencias, narrativas y políticas de diagnóstico y control de la circulación del virus en tres ciudades de diferente escala urbana de Argentina. Realizado en la postpandemia, nuestro análisis se propone aportar al estudio del fenómeno sanitario desde la antropología social, ofreciendo recomendaciones para la planificación y gestión de futuros y probables confinamientos. Concluimos que nuestra contribución como científicas sociales es la comprensión del fenómeno sanitario en el marco de desigualdades estructurales, emergiendo la necesidad de planificar la prevención por confinamiento a escalas micro, meso y macro sociales.

Background The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. Methods and Results This is a prespecified propensity score‐matched analysis from a prospective multicentric real‐world study (READAPT [Real‐Life Study on Short‐Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90‐day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90‐day risk of stroke and other vascular events and 24‐hour early neurological improvement or deterioration (≥2‐point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI −2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98–1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41–0.79]; P

Glyphosate, an herbicide largely used in various contexts, can have adverse effects on human health. Although it is currently the most applied pesticide worldwide, few studies evaluated the extent of human exposure via biomonitoring. To expand such information, biological monitoring of exposure to glyphosate was conducted.The study has a before-and-after design to demonstrate the immediate impact of short-term interventions. Accordingly, the urine concentrations of glyphosate and its main biodegradation product (amino-methylphosphonic acid- AMPA) were measured before and the day after the single herbicide application in 17 male winegrowers. Urine samples were analyzed by high performance liquid chromatography coupled with a triple quadrupole mass spectrometer equipped with an electrospray ionization source.Glyphosate and AMPA were not detectable in pre-application urine samples (limit of quantification for glyphosate (LOQG) was 0.1 μg/L; limit of quantification for AMPA (LOQAMPA) was 0.5 μg/L). After application, glyphosate urinary levels were above LOQG in all workers. The median, min, and max values were 2.30, 0.51, and 47.2 μg/L, respectively. The same values were found for 50 %, 5 % and 95 % percentiles. After assigning numerical values, such as one half the LOQ, to each of the non-detects, the “z” of Wilcoxon matched-pairs signed-ranks test was −3.62 (p = 0.0003), suggesting the pre-application values being significantly lower than the post-application urinary glyphosate concentration. A similar analysis was not feasible with AMPA urinary levels, which were detectable only in 3 workers, after application. 12 (71 %) workers were significantly exposed to glyphosate, but adherence to the adoption of personal protective equipment was good: 14 (82 %) workers used gloves, 13 (76 %) used overalls and 13 (76 %) facial masks.Our data show that glyphosate can be absorbed by the workers after a single application and confirms the usefulness of biomonitoring in exposed workers. Further studies are needed in larger working populations and with multiple glyphosate applications, as well as to evaluate the correlations of glyphosate urine levels with exposure questionnaire data, in order to assess the actual relevance of risk and protection factors.

Hardware-based acceleration approaches for Machine Learning (ML) workloads have been embracing the significant potential of post-CMOS switching devices to attain reduced footprint and/or energy-efficient execution relative to transistor-based GPU and/or TPU-based accelerator architectures. Meanwhile, the promulgation of fabless IC chip manufacturing paradigms has heightened the hardware security concerns inherent in such approaches. Namely, unauthorized access to various supply chain stages may expose significant vulnerabilities resulting in malfunctions including subtle adversarial outcomes via the malicious generation of differentially-corrupted outputs. Whereas the Spin-Orbit Torque Magnetic Tunnel Junction (SOT-MTJ) is a leading spintronic device for use in ML accelerators, as well as holding security tokens, their manufacturing-only security exposures are identified and evaluated herein. Results indicate a novel vulnerability profile whereby an adversary without access to the circuit netlist could differentially-influence the machine learning application’s behavior. Specifically, ML recognition outputs can be significantly swayed via a global modification of oxide thickness (Tox) resulting in bit-flips of the weights in the crossbar array, thus corrupting the recognition of selected digits in MNIST dataset differentially creating an opportunity for an adversary. With just 0.05% of bits in crossbar having a flipped resistance state, digits “4” and “5” show the highest overall error rates, and digit “9” exhibit the lowest impact, with recognition accuracy of digits “2,” “3,” and “8” unaffected by changing the oxide thickness of SOT-MTJs uniformly from 0.75 nm to 1.2 nm without modifying the netlist nor even having access to the circuit design itself. Exposures and mitigation approaches to such novel and potentially damaging manufacturing-side intrusions are identified, postulated, and quantitatively assessed.

Antimicrobial resistance in urinary tract infections (UTIs) is a major public health concern. This study aims to characterize the phenotypic and genetic basis of multidrug resistance (MDR) among expanded-spectrum cephalosporin-resistant (ESCR) uropathogenic Escherichia coli (UPEC) causing UTIs in California patient populations. Between February and October 2019, 577 ESCR UPEC isolates were collected from patients at 6 clinical laboratory sites across California. Lineage and antibiotic resistance genes were determined by analysis of whole-genome sequence data. The lineages ST131, ST1193, ST648, and ST69 were predominant, representing 46%, 5.5%, 4.5%, and 4.5% of the collection, respectively. Overall, 527 (91%) isolates had an expanded-spectrum β-lactamase (ESBL) phenotype, with blaCTX-M-15, blaCTX-M-27, blaCTX-M-55, and blaCTX-M-14 being the most prevalent ESBL genes. In the 50 non-ESBL phenotype isolates, 40 (62%) contained blaCMY-2, which was the predominant plasmid-mediated AmpC (pAmpC) gene. Narrow-spectrum β-lactamases, blaTEM-1B and blaOXA-1, were also found in 44.9% and 32.1% of isolates, respectively. Among ESCR UPEC isolates, isolates with an ESBL phenotype had a 1.7-times-greater likelihood of being MDR than non-ESBL phenotype isolates (P < 0.001). The cooccurrence of blaCTX-M-15, blaOXA-1, and aac(6')-Ib-cr within ESCR UPEC isolates was strongly correlated. Cooccurrence of blaCTX-M-15, blaOXA-1, and aac(6')-Ib-cr was associated with an increased risk of nonsusceptibility to piperacillin-tazobactam, cefepime, fluoroquinolones, and amikacin as well as MDR. Multivariate regression revealed the presence of blaCTX-M-55, blaTEM-1B, and the ST131 genotype as predictors of MDR. IMPORTANCE The rising incidence of resistance to expanded-spectrum cephalosporins among Escherichia coli strains, the most common cause of UTIs, is threatening our ability to successfully empirically treat these infections. ESCR E. coli strains are often MDR; therefore, UTI caused by these organisms often leads to treatment failure, increased length of hospital stay, and severe complications (D. G. Mark, Y.-Y. Hung, Z. Salim, N. J. Tarlton, et al., Ann Emerg Med 78:357-369, 2021, https://doi.org/10.1016/j.annemergmed.2021.01.003). Here, we performed an in-depth analysis of genetic factors of ESCR E. coli associated with coresistance and MDR. Such knowledge is critical to advance UTI diagnosis, treatment, and antibiotic stewardship.

BackgroundEven though the optimal management of a moderate or large residual shunt following patent foramen ovale (PFO) closure is open to question, recent data confirmed that it is associated with an increased risk of stroke recurrence.Case summaryA 48-year-old woman, a migraineur with visual aura, was diagnosed with a PFO associated with a huge multifenestrated atrial septal aneurysm (mfASA) and a moderate right-to-left shunt, detectable only after a Valsalva maneuver on contrast-transthoracic echocardiography. Brain magnetic resonance imaging showed a 1-mm silent white matter lesion in the right frontal lobe. Although the indication was not supported by guidelines, a transcatheter PFO closure was performed at another center with implantation of a large, equally sized, double-disc device (Figulla UNI 33/33 mm). At 6-month follow-up, a 2D/3D transesophageal echocardiography (TEE) color Doppler showed incorrect orientation of the device, which was not parallel to the interatrial septum, with two discs failing to capture the aortic muscular rim and partially protruding in the right atrium; furthermore, a 4 mm × 7 mm ASA fenestration was documented with a residual bidirectional shunt. Thereafter, the same team performed a minimally invasive cardiac surgery under femoro-femoral cardiopulmonary bypass; however, the procedure proved ineffective and was complicated by postoperative pericarditis with pericardial effusion, requiring further rehospitalization 1 month later due to persistent pericarditis, bilateral pleuritis, phrenic nerve palsy, and atrial flutter, which was treated with amiodarone. The patient asked for a second opinion, and our multidisciplinary heart team decided to offer a percutaneous redo intervention. An uneventful implantation of a regular PFO occluder (Figulla Flex II 16/18 mm) across the septal defect was performed successfully. Twelve-month follow-up with 2D TTE color Doppler and contrast transcranial Doppler showed correct position and good interaction between the two devices, with no residual shunt.DiscussionIn addition to the incorrect indication for PFO closure and the failure of minimally invasive surgery, the procedural mishap in this case could have been due to the inappropriate implantation of the first large device within the tunnel. It would have been better to deploy the same large device in the most central fenestration, covering the PFO and a greater part of the remaining mfASA at the same time.

Objective: To evaluate, in the scenario of rapid infusion, the effectiveness of the different regimens of supportive therapy employed in the prevention of nephrotoxicity and electrolyte depletion induced by cisplatin (CDDP). Methods: Data from patients who used CDDP weekly (30 to 40mg/m2) with an infusion time of 60-120 minutes were analyzed. The regimens evaluated were: saline solution (A), saline solution and mannitol (B), saline solution and magnesium (C) and saline solution with mannitol and magnesium (D). The following laboratory parameters were evaluated: creatinine (Cr), magnesium (Mg) sodium (Na) and potassium (K), and glomerular filtration rate (GFR). They were subsequently compiled in Microsoft Office Excel® and analyzed in Software R, using with analysis by means of descriptive statistics, developed in accordance with the recommendations of Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement. Results: The study population evaluated were 46 patients, who received 218 infusions of CDDP. It was observed that schemes A and B had a progressive decrease in Mg. Scheme B had decreased levels of K, Cr and increased Na. In the individual analysis of each cycle, the different schemes of supportive therapy in rapid infusion were equally effective in preventing nephrotoxicity and electrolyte depletion. The schemes used were evaluated for throughout CDDP administrations, the regimen C and D demonstrated efficacy in maintaining renal function throughout multiple administration of CDDP. Conclusion: In the analysis of cumulative doses, regimen C proved to be effective in preserving renal function throughout CDDP administrations. In the individual analysis of each cycle, regardless of the number of times CDDP was administered, protocols C and D, which contained Mg supplementation associated or not with mannitol, were equally effective in preventing nephrotoxicity.

Visna/Maedi virus (VMV) is lentiviral disease of sheep responsible for severe production losses. Multiple genomic regions associated with infection were reported indicating genetic complexity. In this study, a combined genome-wide approach using a high-density SNP array has been performed, comparing VMV-infected (n = 78) and non-infected (n = 66) individuals of the Valle del Belice breed. The serological tests showed a seroprevalence of 26%. The comparison among results from different approaches (GWAS, Fisher’s exact test and the FST analysis) revealed two association signals: on OAR03 close to the GRIN2B gene and on OAR05 close to the TMEM232 gene. To the best of our knowledge, there has been no previous association between these genes and lentiviral infection in any species. The GRIN2B gene plays a role in pain response, synaptic transmission, and receptor clustering, while TMEM232 is involved in the development of immune-related disorders. The results highlighted new aspects of the genetic complexity related to the resistance/susceptibility to VMV in sheep, confirming that studies on different breeds can lead to different results. The ideal approach for validation of the markers identified in our study is to use samples from a population independent from the discovery population with the same phenotype used in the discovery stage.

Local livestock breeds play a crucial role in global biodiversity, connecting natural and human-influenced environments and contributing significantly to ecosystem services. While commercial breeds dominate industrial systems, local livestock breeds in developing countries, like Barbarine sheep in Tunisia, are vital for food security and community maintenance. The Tunisian Barbarine sheep, known for its adaptability and distinctive fat-tailed morphology, faces challenges due to historical crossbreeding. In this study, the Illumina Ovine SNP50K BeadChip array was used to perform a genome-wide characterization of Tunisian Barbarine sheep to investigate its genetic diversity, the genome structure, and the relationship within the context of Mediterranean breeds. The results show moderate genetic diversity and low inbreeding. Runs of Homozygosity analysis find genomic regions linked to important traits, including fat tail characteristics. Genomic relationship analysis shows proximity to Algerian thin-tailed breeds, suggesting crossbreeding impacts. Admixture analysis reveals unique genetic patterns, emphasizing the Tunisian Barbarine’s identity within the Mediterranean context and its closeness to African breeds. Current results represent a starting point for the creation of monitoring and conservation plans. In summary, despite genetic dilution due to crossbreeding, the identification of genomic regions offers crucial insights for conservation. The study confirms the importance of preserving unique genetic characteristics of local breeds, particularly in the face of ongoing crossbreeding practices and environmental challenges. These findings contribute valuable insights for the sustainable management of this unique genetic reservoir, supporting local economies and preserving sheep species biodiversity.

Abstract Background The nationally determined contribution (NDC) presented by Argentina within the framework of the Paris Agreement is aligned with the decisions made in the context of the United Nations Framework Convention on Climate Change (UNFCCC) on the reduction of emissions derived from deforestation and forest degradation, as well as forest carbon conservation (REDD+). In addition, climate change constitutes one of the greatest threats to forest biodiversity and ecosystem services. However, the soil organic carbon (SOC) stocks of native forests have not been incorporated into the Forest Reference Emission Levels calculations and for conservation planning under climate variability due to a lack of information. The objectives of this study were: (i) to model SOC stocks to 30 cm of native forests at a national scale using climatic, topographic and vegetation as predictor variables, and (ii) to relate SOC stocks with spatial–temporal remotely sensed indices to determine biodiversity conservation concerns due to threats from high inter-annual climate variability. Methods We used 1040 forest soil samples (0–30 cm) to generate spatially explicit estimates of SOC native forests in Argentina at a spatial resolution of approximately 200 m. We selected 52 potential predictive environmental covariates, which represent key factors for the spatial distribution of SOC. All covariate maps were uploaded to the Google Earth Engine cloud-based computing platform for subsequent modelling. To determine the biodiversity threats from high inter-annual climate variability, we employed the spatial–temporal satellite-derived indices based on Enhanced Vegetation Index (EVI) and land surface temperature (LST) images from Landsat imagery. Results SOC model (0–30 cm depth) prediction accounted for 69% of the variation of this soil property across the whole native forest coverage in Argentina. Total mean SOC stock reached 2.81 Pg C (2.71–2.84 Pg C with a probability of 90%) for a total area of 460,790 km2, where Chaco forests represented 58.4% of total SOC stored, followed by Andean Patagonian forests (16.7%) and Espinal forests (10.0%). SOC stock model was fitted as a function of regional climate, which greatly influenced forest ecosystems, including precipitation (annual mean precipitation and precipitation of warmest quarter) and temperature (day land surface temperature, seasonality, maximum temperature of warmest month, month of maximum temperature, night land surface temperature, and monthly minimum temperature). Biodiversity was influenced by the SOC levels and the forest regions. Conclusions In the framework of the Kyoto Protocol and REDD+, information derived in the present work from the estimate of SOC in native forests can be incorporated into the annual National Inventory Report of Argentina to assist forest management proposals. It also gives insight into how native forests can be more resilient to reduce the impact of biodiversity loss.

Abstract Background The presence of goats in the Canary Islands dates back to the late 1st millennium BC, which coincides with the colonization by the Amazigh settlers. However, the exact geographic origin of Canarian goats is uncertain since the Amazigh peoples were distributed over a wide spatial range. Nowadays, three Canarian breeds (Palmera, Majorera and Tinerfeña) are officially recognized, along with two distinct South and North Tinerfeña ecotypes, with the South Tinerfeña and Majorera goats thriving in arid and dry semi-desertic environments and the Palmera and North Tinerfeña goats are adapted to humid and temperate areas that are influenced by trade winds. Genotypes for 224 Canarian goats were generated using the Illumina Goat single nucleotide polymorphism (SNP)50 BeadChip. By merging these data with the genotypes from 1007 individuals of African and Southern European ancestry, our aim was to ascertain the geographic origin of the Canarian goats and identify genes associated with adaptation to diverse environmental conditions. Results The diversity indices of the Canarian breeds align with most of those of the analyzed local breeds from Africa and Europe, except for the Palmera goats that showed lower levels of genetic variation. The Canarian breeds demonstrate a significant genetic differentiation compared to other populations, which indicates a history of prolonged geographic isolation. Moreover, the phylogenetic reconstruction indicated that the ancestry of the Canarian goats is fundamentally North African rather than West African. The ADMIXTURE and the TreeMix analyses showed no evidence of gene flow between Canarian goats and other continental breeds. The analysis of runs of homozygosity (ROH) identified 13 ROH islands while the window-based FST method detected 25 genomic regions under selection. Major signals of selection were found on Capra hircus (CHI) chromosomes 6, 7, and 10 using various comparisons and methods. Conclusions This genome-wide analysis sheds new light on the evolutionary history of the four breeds that inhabit the Canary Islands. Our findings suggest a North African origin of the Canarian goats. In addition, within the genomic regions highlighted by the ROH and FST approaches, several genes related to body size and heat tolerance were identified.

Abstract Heterozygosity-rich regions (HRR) are genomic regions of high heterozygosity, which may harbor loci related to key functional traits such as immune response, survival rate, fertility, and other fitness traits. This study considered 30 Italian and 19 worldwide goat breeds genotyped with the Illumina GoatSNP50k BeadChip. The aim of the work was to study inter-breed relationships and HRR patterns using Sliding Window (SW) and Consecutive Runs (CR) detection methods. Genetic relationships highlighted a clear separation between non-European and European breeds, as well as the north–south geographic cline within the latter. The Pearson correlation coefficients between the descriptive HRR parameters obtained with the SW and CR methods were higher than 0.9. A total of 166 HRR islands were detected. CHI1, CHI11, CHI12 and CHI18 were the chromosomes harboring the highest number of HRR islands. The genes annotated in the islands were linked to various factors such as productive, reproductive, immune, and environmental adaptation mechanisms. Notably, the Montecristo feral goat showed the highest number of HRR islands despite the high level of inbreeding, underlining potential balancing selection events characterizing its evolutionary history. Identifying a species-specific HRR pattern could provide a clearer view of the mechanisms regulating the genome modelling following anthropogenic selection combined with environmental interaction.

Abstract Background During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. Methods Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. Results A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. Conclusions PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

La pratique du semis direct (SD), en tant que composante principale de l’agriculture de conservation (AC), vise à améliorer la qualité des sols et la productivité des cultures. Les avantages des légumineuses cultivées sous le système SD pourraient être encore améliorés en utilisant des génotypes performants qui agissent positivement sur la disponibilité des éléments nutritifs dans le sol. Dans ce sens, la présente étude vise à évaluer les propriétés chimiques du sol après la récolte de certains génotypes de lentille et de pois chiche, dans des systèmes semis conventionnel (SC) et semis direct (SD). Les propriétés évaluées comprennent le pH du sol, le phosphore disponible (P), le potassium échangeable (K), la teneur en nitrates (NO3), l’azote total (TotN) et la matière organique du sol (MOS) à environ 30 cm de profondeur. Le semis de pois chiche sous le système SD a augmenté de manière significative le P, le K, le NO3 et le TotN du sol de 8 %, 17 %, 54 % et 13 % respectivement, tandis que le pH du sol a légèrement diminué de 3 %, avec un effet non pertinent sur la MOS. Toutes les propriétés chimiques du sol ont enregistré une corrélation négative avec le pH du sol. En conséquence, les génotypes les plus répondeurs au système SD pour la culture de pois chiche étaient le génotype 71771 qui a amélioré les niveaux de P et de K de 40 % et 30 %, respectivement, et le génotype PI269882 qui a amélioré le NO3 et le TotN de 55 % et 27 %, respectivement, de même le génotype PI564775 a amélioré le K et le NO3 de 17 % et 80 %, respectivement. De l’autre côté, les génotypes les plus répondeurs au SD pour la culture de lentille étaient le génotype ZR-7 qui a amélioré les niveaux de P et de K de 25 % et 10 %, respectivement, et le génotype LR8 qui a amélioré le NO3 de 41 %. En conclusion, l’utilisation des génotypes de légumineuses les plus adaptés au système semis direct pourrait être une alternative prometteuse pour améliorer encore davantage la fertilité des sols et la productivité des cultures.

Abstract Purpose To assess the prevalence of alterations in anthropometric parameters predictive of metabolic syndrome and cardiovascular risk among childhood brain tumor survivors. Methods Anthropometric parameters predictive of metabolic syndrome and cardiovascular risk were analyzed [height, weight, BMI, waist circumference, hip circumference, waist-height ratio (WHtR), waist-hip ratio (WHR, blood pressure] of 25 patients who survived childhood brain tumors. Results 21 patients (84%) showed alteration of at least one predictive anthropometric parameter. 11 patients (44%) showed a BMI > 75th percentile and 19 patients (76%) showed a pathological WHR value. A pathological WHtR (> 0.5), was identified in 17 patients (68%); the average WHtR observed was 0.53. 9 patients (36%) showed an alteration of all three anthropometric parameters considered. Comparing this subpopulation with the subpopulation with less than three altered parameters, a greater prevalence of the combined alteration was observed in the female sex compared to the male sex (67% vs. 26%). No significant differences were observed regarding the age of diagnosis and end of treatment nor the treatments carried out (chemotherapy, radiotherapy, steroid therapy) between the two groups. Conclusion These results suggest that this population is at high risk of presenting pathological values of BMI, WHR and WHtR with consequent high risk of developing metabolic syndrome and cardiovascular diseases.

Abstract There are several overlapping clinical practice guidelines in acute pancreatitis (AP), however, none of them contains suggestions on patient discharge. The Hungarian Pancreatic Study Group (HPSG) has recently developed a laboratory data and symptom-based discharge protocol which needs to be validated. (1) A survey was conducted involving all members of the International Association of Pancreatology (IAP) to understand the characteristics of international discharge protocols. (2) We investigated the safety and effectiveness of the HPSG-discharge protocol. According to our international survey, 87.5% (49/56) of the centres had no discharge protocol. Patients discharged based on protocols have a significantly shorter median length of hospitalization (LOH) (7 (5;10) days vs. 8 (5;12) days) p

Maedi Visna (MV) is a viral infection in sheep caused by Lentivirus and characterised by a long incubation period, slow progression, weight loss and eventually death. TMEM154 was reported in the ovine as major candidate gene associated with host susceptibility/resistance. The aim of this study was to verify the prevalence of MV infection within Sicilian herds of Valle del Belìce breed using an ELISA serological test and to estimate the frequencies of the resistant/susceptible genotypes to the TMEM154 gene. Finally, we investigated the association between TMEM154 E/K genotype and MV infectious status. A total of 1,083 animals from different flocks were tested. The ELISA method showed 15.33% (n = 166) of infected individuals. Analyses of the sequences showed the presence of both K and E alleles with frequencies of 0.151 and 0.849, respectively. On the total individuals, only 23 carried KK genotype while 280 were heterozigous EK, and 780 homozygous EE. The locus was in Hardy-Weinberg equilibrium in the breed (p-value

Italy has a long history of sheep breeding and counts several local populations that may represent a unique source of genetic diversity. Among these, Nera del Mela is a sheep genetic resource historically reared in Sicily but not officially recognised as a breed. In this study, we genotyped 36 individuals of Nera del Mela using the OvineSNP50K array, in order to estimate the genetic diversity and evaluate the population structure and relatedness with other Italian sheep breeds. Genetic diversity indices, and inbreeding estimated from runs of homozygosity (FROH) revealed a moderate level of variability. Runs of homozygosity islands mapped candidate genes involved in the adaptation to local environment and immune response. Population genetic analyses using different approaches highlighted the hypothesis that this sheep possesses a defined genetic structure, especially if compared with other recognised breeds, despite the influence of other populations such as the Sicilian breeds. Overall, our findings represent a starting point for the possible official acknowledgement of this population, for the creation of a conservation plan, and thus for preserving this genomic heritage.HIGHLIGHTS Nera de Mela sheep can be considered as a reservoir of genetic diversity. The results indicated a clear genetic differentiation from other populations and moderate level of genetic variability. Our findings represent a starting point for the creation of conservation plans.

Background/Objectives: Levothyroxine (L-T4) is available for use in congenital hypothyroidism (CH) in three formulations: tablets, drops, and oral solution. This study aims to compare the efficacy and safety of all three L-T4 formulations. Methods: We enrolled 63 children born between January 2019 and April 2023 in the Emilia-Romagna Region (Italy) and diagnosed with CH by newborn screening. They were divided according to the L-T4 formulation used: drops (Group D), oral solution (Group S), and tablets (Group T). Clinical and laboratory data were collected up to 3 years after the start of replacement therapy. Results: Serum-free thyroxine (sFT4) and thyroid stimulating hormone (sTSH) normalization occurred within the first month of treatment in most patients of all groups. No negative effects on growth and cognitive development were observed. At 7–15 days we found higher median sTSH levels (p = 0.031) and a greater percentage of patients with sTSH > 5 µU/mL (p = 0.011) in Group S than in Group T, but comparable sFT4 levels. At 12 months, a greater percentage of patients of Group D showed sFT4 values below the normal range than Group S (p = 0.011) and Group T (p = 0.038); Conclusions: Overall, our study reported an equal efficacy of the L-T4 oral solution compared to drops and tablets in CH treatment. A larger series of patients and a long-term follow-up are needed.

The carbon source/sink nature and the water balance of a drip-irrigated and mulched watermelon cultivated under a semi-arid climate were investigated. Biodegradable films, plants and some fruits were left on the soil as green manure. The study spanned from watermelon planting to the subsequent crop (June–November 2023). The eddy covariance technique was employed to monitor water vapor (H2O) and carbon dioxide (CO2) fluxes, which were partitioned into transpiration, evaporation, photosynthesis and respiration, respectively, using the flux variance similarity method.This method utilizesthe Monin–Obukhov similarity theory to separate stomatal (photosynthesis and transpiration) from non-stomatal (respiration and evaporation) processes. The results indicate that mulching films contribute to carbon sequestration in the soil (+19.3 g C m−2). However, the mulched watermelon crop presented in this study functions as a net carbon source, with a net biome exchange, representing the net rate of C accumulation in or loss from ecosystems, equal to +230 g C m−2. This is primarily due to the substantial amount of carbon exported through marketable fruits. Fixed water scheduling led to water waste through deep percolation (approximately 1/6 of the water supplied), which also contributed to the loss of organic carbon via leaching (−4.3 g C m−2). These findings recommend further research to enhance the sustainability of this crop in terms of both water and carbon balances.

Over the last several years, a growing body of evidence from anatomical, physiological, and functional neuroimaging studies has increasingly indicated that the cerebellum is actively involved in managing higher order cognitive functions and regulating emotional responses. It has become clear that when children experience congenital or acquired cerebellar lesions, these injuries can lead to a variety of cognitive and emotional disorders, manifesting in different combinations. This underscores the cerebellum’s essential role not only throughout developmental stages but particularly in facilitating learning processes, highlighting its critical importance beyond its traditional association with motor control. Furthermore, the intricate neural circuits within the cerebellum are believed to contribute to the fine-tuning of motor actions and coordination but are also increasingly recognized for their involvement in cognitive processes such as attention, language, and problem solving. Recent research has highlighted the importance of cerebellar health and integrity for optimal functioning across various domains of the human experience.

The AurkA serine/threonine kinase is a key regulator of cell division controlling mitotic entry, centrosome maturation, and chromosome segregation. The microtubule-associated protein TPX2 controls spindle assembly and is the main AurkA regulator, contributing to AurkA activation, localisation, and stabilisation. Since their identification, AurkA and TPX2 have been described as being overexpressed in cancer, with a significant correlation with highly proliferative and aneuploid tumours. Despite the frequent occurrence of AurkA/TPX2 co-overexpression in cancer, the investigation of their involvement in tumorigenesis and cancer therapy resistance mostly arises from studies focusing only on one at the time. Here, we review the existing literature and discuss the mitotic phenotypes described under conditions of AurkA, TPX2, or AurkA/TPX2 overexpression, to build a picture that may help clarify their oncogenic potential through the induction of chromosome instability. We highlight the relevance of the AurkA/TPX2 complex as an oncogenic unit, based on which we discuss recent strategies under development that aim at disrupting the complex as a promising therapeutic perspective.