Extracellular Vesicles: The Next Generation of Biomarkers and Treatment for Central Nervous System Diseases.

It has been widely established that the characterization of extracellular vesicles (EVs), particularly small EVs (sEVs), shed by different cell types into biofluids, helps to identify biomarkers and therapeutic targets in neurological and neurodegenerative diseases. Recent studies are also exploring the efficacy of mesenchymal stem cell-derived extracellular vesicles naturally enriched with therapeutic microRNAs and proteins for treating various diseases. In addition, EVs released by various neural cells play a crucial function in the modulation of signal transmission in the brain in physiological conditions. However, in pathological conditions, such EVs can facilitate the spread of pathological proteins from one brain region to the other. On the other hand, the analysis of EVs in biofluids can identify sensitive biomarkers for diagnosis, prognosis, and disease progression. This review discusses the potential therapeutic use of stem cell-derived EVs in several central nervous system diseases. It lists their differences and similarities and confers various studies exploring EVs as biomarkers. Further advances in EV research in the coming years will likely lead to the routine use of EVs in therapeutic settings.

Fungal Osteomyelitis of the Hip with Septic Arthritis: Case Report.

Fungal osteomyelitis, especially associated with septic arthritis, is uncommon in Brazil; therefore, sometimes it is difficult to diagnose and treat it. We report the case of a young patient, with no immunosuppressive risk factor, with osteomyelitis leading to septic arthritis of the hip. The diagnosis was performed after surgical drainage and visualization of Cryptococcus neoformans at pathological anatomy. Antifungal treatment resulted in complete remission of the symptoms. Since there is no consensus on the treatment of fungal osteomyelitis, this case report aims to inform orthopedists about the importance of hip arthritis differential diagnosis and the good evolution of clinical treatment after drainage and pathogen isolation.

Sutura em Polia Retificada para síntese de feridas de pele tensionadas / Rectified Pulley Suture for the synthesis of tensioned skin wounds

Introdução: A síntese de feridas de pele tensionadas é uma área que tem sido alvo de estudos para o desenvolvimento de técnicas de sutura que sejam capazes de realizar o fechamento primário dessas feridas com alívio de tensão, garantindo uma cicatrização adequada e evitando complicações como deiscência, edema, sangramento e infecção. Método: Esta pesquisa tratou-se de um estudo piloto, sendo a primeira apresentação da técnica de Sutura em Polia Retificada para síntese de feridas de pele tensionadas através do acompanhamento prospectivo, duplo-cego, de uma série de casos de 8 pacientes randomicamente admitidos no centro cirúrgico de um hospital de alta complexidade de uma cidade de médio porte. Resultados: A Sutura em Polia Retificada é uma técnica versátil e apta para lidar com feridas de pele tensionadas, uma vez que no intraoperatório conseguiu fechar por primeira intenção lesões de até 6,5 centímetros e de diferentes regiões tensionadas sem necessidade do uso de técnicas mais complexas, como retalhos, enxertos, zetaplastia e fechamento por segunda intenção. Além disso, no pós-operatório, houve redução dos escores da POSAS, indicando um processo de cicatrização satisfatório tanto para os observadores quanto para o paciente. É imprescindível mencionar, também, que o desfecho mais temido no seguimento dos pacientes com feridas tensionadas submetidos a fechamento primário - a deiscência - foi completamente evitado. Conclusão: A técnica é simples, confiável, segura e reprodutível, com curta curva de aprendizagem, de forma que a Sutura em Polia Retificada pode ser considerada como uma nova ferramenta a ser integrada ao arsenal cirúrgico.

Introduction: The synthesis of tensioned skin wounds is an area that has been the subject of studies for the development of suturing techniques that are capable of performing the primary closure of these wounds with tension relief, ensuring adequate healing, and avoiding complications such as dehiscence, edema, bleeding, and infection. Method: This research was a pilot study, being the first presentation of the Rectified Pulley Suture technique for the synthesis of tensioned skin wounds through prospective, double-blind monitoring of a series of cases of 8 patients randomly admitted to the surgical center of a high-complexity hospital in a mediumsized city. Results: Rectified Pulley Suture is a versatile technique suitable for dealing with tensioned skin wounds, since intraoperatively it was able to close, by first intention, lesions measuring up to 6.5 centimeters and in different tensioned regions without the need for the use of more extensive techniques. complex, such as flaps, grafts, Z-plasty, and secondary intention closure. Furthermore, post-operatively, there was a reduction in POSAS scores, indicating a satisfactory healing process for both observers and the patient. It is also essential to mention that the most feared outcome in the follow-up of patients with tension wounds undergoing primary closure - dehiscence - was completely avoided. Conclusion: The technique is simple, reliable, safe, and reproducible, with a short learning curve, so the Rectified Pulley Suture can be considered a new tool to be integrated into the surgical arsenal.

Potential antitumor effects of short-chain fatty acids in breast cancer models.

The effects of short-chain fatty acids (SCFAs) have been explored against cancer due to the crosstalk between gut microbiota alterations and the immune system as a crucial role in cancer development. We evaluated the SCFAs effects in both in vitro and in vivo breast cancer models. In vitro, the SCFAs displayed contrasting effects on viability index, according to the evaluation of breast cancer cells with different phenotypes, human MCF-7, SK-BR-3, MDA-MD-231, or the mouse 4T1 lineage. Acetate displayed minimal effects at concentrations up to 100 mM. Alternatively, propionate increases or reduces cell viability depending on the concentration. Butyrate and valerate showed consistent time- and concentration-dependent effects on the viability of human or mouse breast cancer cells. The selective FFA2 4-CMTB or FFA3 AR420626 receptor agonists failed to overtake the SCFA actions, except by modest inhibitory effects on MDA-MB-231 and 4T1 cell viability. The FFA2 CATPB or FFA3 and ß-hydroxybutyrate receptor antagonists lacked significant activity on human cell lines, although CATPB reduced 4T1 cell viability. Butyrate significantly affected cell morphology, clonogenicity, and migration, according to the evaluation of MDA-MB-231 and 4T1 cells. A preliminary examination of in vivo oral effects of butyrate, propionate, or valerate, dosed in prophylactic or therapeutic regimens, on several parameters evaluated in an orthotopic breast cancer model showed a reduction of lung metastasis in post-tumor induction butyrate-treated mice. Overall, the present results indicate that in vitro effects of SCFAs did not rely on FFA2 or FFA3 receptor activation, and they were not mirrored in vivo, at least at the tested conditions. Overall, the present results indicate potential in vitro inhibitory effects of SCFAs in breast cancer, independent of FFA2 or FFA3 receptor activation, and, in the metastatic breast cancer model, the butyrate-dosed therapeutic regimen reduced the number of lung metastases.

Renal screening sonography-A comparative study in a Portuguese basic emergency service.

INTRODUCTION: Renal Point-of-Care Ultrasound (POCUS) is a screening modality that aids in clinical decision-making for patients with suspected renal colic. This study intends to compare the accuracy and pertinence of sonographic findings obtained by a sonographer in a Basic Emergency Service (BES) with the imaging findings at the Referral Hospital (RH). METHODS: Thirty-one patients suspected of having renal pathology underwent initial sonography screening with POCUS at the BES and were subsequently referred to the RH for additional imaging examinations. The results of both examinations were compared to verify whether the findings from the BES were confirmed by the radiologist in the RH and to ensure that the patient referrals from BES to RH were appropriate. RESULTS: In our sample, the majority of patients (80%) exhibited varying degrees of pyelocaliceal distension, with nearly half (48%) patients presenting obstructions. A strong association between the sonographic findings in the BES and the RH was found in the variables 'Dilatation of pyelocaliceal system' (V = 0.895; P = 0.00), 'Simple cystic formation' (V = 0.878; P = 0.000), respectively. There was a statistically significant correlation between BES and RH findings, indicating a strong association between these two variables, respectively (k = 0.890; P = 0.000) and (k = 0.870; P = 0.000). There was also a strong statistically significant correlation in the ultrasonographic findings between BES and RH performers (k = 0.890; P = 0.000 and k = 0.870; P = 0.000). In this research, an achieved sensitivity of 96% and a specificity of 85% were demonstrated in the identification of pyelocaliceal dilatation. CONCLUSION: Renal POCUS screening successfully detected abnormalities in the urinary system of patients suspected of having renal colic. The sonographic findings at the BES had a good correlation with the complementary imaging results obtained at the RH in Portugal. These results suggest that Radiographers/Sonographers can have an important role in the preliminary assessment of urgent renal pathology in remote areas, contributing to a correct referral and early treatment.

Evaluation of the effects of the Zika Virus-Immunoglobulin G+ complex on murine microglial cells.

After the Zika virus (ZIKV) epidemic in Brazil, ZIKV infections were linked to damage to the central nervous system (CNS) and congenital anomalies. Due to the virus's ability to cross the placenta and reach brain tissue, its effects become severe, leading to Congenital Zika Syndrome (CZS) and resulting in neuroinflammation, microglial activation, and secretion of neurotoxic factors. The presence of ZIKV triggers an inadequate fetal immune response, as the fetus only has the protection of maternal antibodies of the Immunoglobulin G (IgG) class, which are the only antibodies capable of crossing the placenta. Because of limited understanding regarding the long term consequences of ZIKV infection and the involvement of maternal antibodies, this study sought to assess the impact of the ZIKV + IgG⁺complex on murine microglial cells. The cells were exposed to ZIKV, IgG antibodies, and the ZIKV + IgG⁺complex for 24 and 72 h. Treatment-induced cytotoxic effects were evaluated using the cell viability assay, oxidative stress, and mitochondrial membrane potential. The findings indicated that IgG antibodies exhibit cytotoxic effects on microglia, whether alone or in the presence of ZIKV, leading to compromised cell viability, disrupted mitochondrial membrane potential, and heightened oxidative damage. Our conclusion is that IgG antibodies exert detrimental effects on microglia, triggering their activation and potentially disrupting the creation of a neurotoxic environment. Moreover, the presence of antibodies may correlate with an elevated risk of ZIKV-induced neuroinflammation, contributing to long-term CNS damage.

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

Sequential Evaluation of Hematology Markers as a Prognostic Factor in Glioblastoma Patients.

In our study, we investigated the prognostic significance of hematological markers-NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width-Coefficient of Variation)-in 117 glioblastoma patients. The data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with the overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan-Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in the NLR, PLR, and RDW-CV across different treatment stages. The NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p = 0.007, η2p = 0.06; PLR: p = 0.001, η2p = 0.23), while the RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p < 0.001, η2p = 0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, a higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR = 1.03, p = 0.029; RDW-CV at progression: HR = 1.14, p = 0.004). We proposed specific marker cut-offs that demonstrated significant associations with survival outcomes when applied to Kaplan-Meier survival curves (NLR at 2nd line < 5: p < 0.017; RDW-CV at progression < 15: p = 0.007). An elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management.

Artificial intelligence as a prediction tool for orthognathic surgery assessment.

INTRODUCTION: An ideal orthodontic treatment involves qualitative and quantitative measurements of dental and skeletal components to evaluate patients' discrepancies, such as facial, occlusal, and functional characteristics. Deciding between orthodontics and orthognathic surgery remains challenging, especially in borderline patients. Advances in technology are aiding clinical decisions in orthodontics. The increasing availability of data and the era of big data enable the use of artificial intelligence to guide clinicians' diagnoses. This study aims to test the capacity of different machine learning (ML) models to predict whether orthognathic surgery or orthodontics treatment is required, using soft and hard tissue cephalometric values. METHODS: A total of 920 lateral radiographs from patients previously treated with either conventional orthodontics or in combination with orthognathic surgery were used, comprising n = 558 Class II and n = 362 Class III patients, respectively. Thirty-two measures were obtained from each cephalogram at the initial appointment. The subjects were randomly divided into training (n = 552), validation (n = 183), and test (n = 185) datasets, both as an entire sample and divided into Class II and Class III sub-groups. The extracted data were evaluated using 10 machine learning models and by a four-expert panel consisting of orthodontists (n = 2) and surgeons (n = 2). RESULTS: The combined prediction of 10 models showed top-ranked performance in the testing dataset for accuracy, F1-score, and AUC (entire sample: 0.707, 0.706, 0.791; Class II: 0.759, 0.758, 0.824; Class III: 0.822, 0.807, 0.89). CONCLUSIONS: The proposed combined 10 ML approach model accurately predicted the need for orthognathic surgery, showing better performance in Class III patients.

A randomised, crossover trial exploring the patient perspective and effectiveness of biosimilar adalimumab transition: IBD reference and biosimilar adalimumab cross over study (iBaSS).

BACKGROUND: Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition. AIM: The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5). METHOD: iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24 weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes. RESULTS: A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity. CONCLUSION: This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes. CLINICAL TRIAL REGISTERED WITH EUDRACT: Number 2018-004967-30.

Comparison of the ABC and ACMG systems for variant classification.

The ABC and ACMG variant classification systems were compared by asking mainly European clinical laboratories to classify variants in 10 challenging cases using both systems, and to state if the variant in question would be reported as a relevant result or not as a measure of clinical utility. In contrast to the ABC system, the ACMG system was not made to guide variant reporting but to determine the likelihood of pathogenicity. Nevertheless, this comparison is justified since the ACMG class determines variant reporting in many laboratories. Forty-three laboratories participated in the survey. In seven cases, the classification system used did not influence the reporting likelihood when variants labeled as "maybe report" after ACMG-based classification were included. In three cases of population frequent but disease-associated variants, there was a difference in favor of reporting after ABC classification. A possible reason is that ABC step C (standard variant comments) allows a variant to be reported in one clinical setting but not another, e.g., based on Bayesian-based likelihood calculation of clinical relevance. Finally, the selection of ACMG criteria was compared between 36 laboratories. When excluding criteria used by less than four laboratories (<10%), the average concordance rate was 46%. Taken together, ABC-based classification is more clear-cut than ACMG-based classification since molecular and clinical information is handled separately, and variant reporting can be adapted to the clinical question and phenotype. Furthermore, variants do not get a clinically inappropriate label, like pathogenic when not pathogenic in a clinical context, or variant of unknown significance when the significance is known.

The first confirmed human case of rabies, Timor-Leste, 2024.

In March 2024, the first ever human case of rabies, following a dog bite, was detected in Timor-Leste. This paper briefly discusses the circumstances of transmission, clinical presentation, palliative care of the case and public health measures taken. Timor-Leste was previously considered rabies-free. Any person who is bitten or scratched by an animal that could potentially transmit rabies virus (especially dogs, bats, monkeys or cats) in Timor-Leste should be assessed for consideration of provision of rabies post-exposure prophylaxis.

Development of a new affinity maturation protocol for the construction of an internalizing anti-nucleolin antibody library.

Over the last decades, monoclonal antibodies have substantially improved the treatment of several conditions. The continuous search for novel therapeutic targets and improvements in antibody's structure, demands for a constant optimization of their development. In this regard, modulation of an antibody's affinity to its target has been largely explored and culminated in the discovery and optimization of a variety of molecules. It involves the creation of antibody libraries and selection against the target of interest. In this work, we aimed at developing a novel protocol to be used for the affinity maturation of an antibody previously developed by our group. An antibody library was constructed using an in vivo random mutagenesis approach that, to our knowledge, has not been used before for antibody development. Then, a cell-based phage display selection protocol was designed to allow the fast and simple screening of antibody clones capable of being internalized by target cells. Next generation sequencing coupled with computer analysis provided an extensive characterization of the created library and post-selection pool, that can be used as a guide for future antibody development. With a single selection step, an enrichment in the mutated antibody library, given by a decrease in almost 50% in sequence diversity, was achieved, and structural information useful in the study of the antibody-target interaction in the future was obtained.

Cerebral Venous Thrombosis in Patients With Traumatic Brain Injury: Epidemiology and Outcome.

The natural history and epidemiological aspects of traumatic cerebral venous thrombosis (CVT) are not fully understood. Due to the concomitant occurrence with intracranial hemorrhages, guidelines for medical treatment have been highly controversial. In this study, our objective was to carry out an analysis description of the population and to conduct a literature review. A prospectively gathered radiology registry data of patients hospitalized at the tertiary hospital of Centro Hospitalar Universitário do São João, Porto, Portugal, between 2016 and 2021 was carried out. All patients with traumatic brain injury (TBI) and concomitant CVT were identified. CVT was confirmed by CT venogram. Demographic, clinical, and radiological data and their medical management were reported. In-hospital complications and treatment outcomes were compared between patients measured by the Glasgow Outcome Score Extended (GOSE) at discharge and GOSE at three months. There were 41 patients with traumatic CVT admitted to this study. The majority (45.2%) had a hyperdense signal near the lateral sinus at admission, and only 26.2% presented with skull fractures. Of this cohort, 95% had experienced lateral sinus thrombosis. Twenty-five patients (60%) had occlusive venous thrombosis. Venous infarct was the main complication following CVT. Thirty-two patients (78%) were anticoagulated after CVT and four developed complications. At the three-month follow-up after discharge, 28.2% had good recovery (GOSE > 6). This study revealed a higher incidence of CVT in severe TBI and a mild association with skull fractures. There is a higher incidence of CVT in the lateral sinus. Management was inconsistent, with no difference in outcome without or with anticoagulation. Larger, prospective cohort studies are required to better comprehend this condition and determine evidence-based guidelines.

Balancing Act: Tubulin Glutamylation and Microtubule Dynamics in Toxoplasma gondii.

The success of the intracellular parasite Toxoplasma gondii in invading host cells relies on the apical complex, a specialized microtubule cytoskeleton structure associated with secretory organelles. The T. gondii genome encodes three isoforms of both α- and ß-tubulin, which undergo specific post-translational modifications (PTMs), altering the biochemical and biophysical proprieties of microtubules and modulating their interaction with associated proteins. Tubulin PTMs represent a powerful and evolutionarily conserved mechanism for generating tubulin diversity, forming a biochemical 'tubulin code' interpretable by microtubule-interacting factors. T. gondii exhibits various tubulin PTMs, including α-tubulin acetylation, α-tubulin detyrosination, Δ5α-tubulin, Δ2α-tubulin, α- and ß-tubulin polyglutamylation, and α- and ß-tubulin methylation. Tubulin glutamylation emerges as a key player in microtubule remodeling in Toxoplasma, regulating stability, dynamics, interaction with motor proteins, and severing enzymes. The balance of tubulin glutamylation is maintained through the coordinated action of polyglutamylases and deglutamylating enzymes. This work reviews and discusses current knowledge on T. gondii tubulin glutamylation. Through in silico identification of protein orthologs, we update the recognition of putative proteins related to glutamylation, contributing to a deeper understanding of its role in T. gondii biology.

Is three-piece maxillary segmentation surgery a stable procedure?

Objective: : The number of three-piece maxillary osteotomies has increased over the years; however, the literature remains controversial. The objective of this study was to evaluate the skeletal stability of this surgical modality compared with that of one-piece maxillary osteotomy. Methods: : This retrospective cohort study included 39 individuals who underwent Le Fort I maxillary osteotomies and were divided into two groups: group 1 (three pieces, n = 22) and group 2 (one piece, n = 17). Three cone-beam computed tomography scans from each patient (T1, pre-surgical; T2, post-surgical; and T3, follow-up) were used to evaluate the three-dimensional skeletal changes. Results: : The differences within groups were statistically significant only for group 1 in terms of surgical changes (T2-T1) with a mean difference in the canine region of 3.09 mm and the posterior region of 3.08 mm. No significant differences in surgical stability were identified between or within the groups. The mean values of the differences between groups were 0.05 mm (posterior region) and -0.39 mm (canine region). Conclusions: : Our findings suggest that one- and three-piece maxillary osteotomies result in similar post-surgical skeletal stability.

Antiviral Action against SARS-CoV-2 of a Synthetic Peptide Based on a Novel Defensin Present in the Transcriptome of the Fire Salamander (Salamandra salamandra).

The potential emergence of zoonotic diseases has raised significant concerns, particularly in light of the recent pandemic, emphasizing the urgent need for scientific preparedness. The bioprospection and characterization of new molecules are strategically relevant to the research and development of innovative drugs for viral and bacterial treatment and disease management. Amphibian species possess a diverse array of compounds, including antimicrobial peptides. This study identified the first bioactive peptide from Salamandra salamandra in a transcriptome analysis. The synthetic peptide sequence, which belongs to the defensin family, was characterized through MALDI TOF/TOF mass spectrometry. Molecular docking assays hypothesized the interaction between the identified peptide and the active binding site of the spike WT RBD/hACE2 complex. Although additional studies are required, the preliminary evaluation of the antiviral potential of synthetic SS-I was conducted through an in vitro cell-based SARS-CoV-2 infection assay. Additionally, the cytotoxic and hemolytic effects of the synthesized peptide were assessed. These preliminary findings highlighted the potential of SS-I as a chemical scaffold for drug development against COVID-19, hindering viral infection. The peptide demonstrated hemolytic activity while not exhibiting cytotoxicity at the antiviral concentration.

Thermal properties of nanofluids using hydrophilic and hydrophobic LiYF4:Yb/Er upconverting nanoparticles.

Luminescent nanoparticles have shown great potential for thermal sensing in bio-applications. Nonetheless, these materials lack water dispersibility that can be overcome by modifying their surface properties with water dispersible molecules such as cysteine. Herein, we employ LiYF4:Er3+/Yb3+ upconverting nanoparticles (UCNPs) capped with oleate or modified with cysteine dispersed in cyclohexane or in water, respectively, as thermal probes. Upconversion emission was used to sense temperature with a relative thermal sensitivity of ∼1.24% K-1 (at 300 K) and a temperature uncertainty of 0.8 K for the oleate capped and of 0.5 K for cysteine modified NPs. To study the effect of the cysteine modification in the heat transfer processes, the thermal conductivity of the nanofluids was determined, yielding 0.123(6) W m-1 K-1 for the oleate capped UCNPs dispersed in cyclohexane and 0.50(7) W m-1 K-1 for the cysteine modified UCNPs dispersed in water. Moreover, through the heating curves, the nanofluids' thermal resistances were estimated, showing that the cysteine modification partially prevents heat transfer.

Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure.

STUDY QUESTION: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? SUMMARY ANSWER: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. WHAT IS KNOWN ALREADY: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. STUDY DESIGN, SIZE, DURATION: Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. MAIN RESULTS AND THE ROLE OF CHANCE: This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. LARGE SCALE DATA: GWAS data are available from the authors upon reasonable request. LIMITATIONS, REASONS FOR CAUTION: Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the "Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)" (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/ AEI/10.13039/501100011033), and the 'Proyectos I+D+i del Programa Operativo FEDER 2020' (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.