Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

CT-guided High-Dose-Rate Brachytherapy versus Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma.

Background CT-guided high-dose-rate (HDR) brachytherapy (hereafter, HDR brachytherapy) has been shown to be safe and effective for patients with unresectable hepatocellular carcinoma (HCC), but studies comparing this therapy with other local-regional therapies are scarce. Purpose To compare patient outcomes of HDR brachytherapy and transarterial chemoembolization (TACE) in patients with unresectable HCC. Materials and Methods This multi-institutional retrospective study included consecutive treatment-naive adult patients with unresectable HCC who underwent either HDR brachytherapy or TACE between January 2010 and December 2022. Overall survival (OS) and progression-free survival (PFS) were compared between patients matched for clinical and tumor characteristics by propensity score matching. Not all patients who underwent TACE had PFS available; thus, a different set of patients was used for PFS and OS analysis for this treatment. Hazard ratios (HRs) were calculated from Kaplan-Meier survival curves. Results After propensity matching, 150 patients who underwent HDR brachytherapy (median age, 71 years [IQR, 63-77 years]; 117 males) and 150 patients who underwent TACE (OS analysis median age, 70 years [IQR, 63-77 years]; 119 male; PFS analysis median age, 68 years [IQR: 63-76 years]; 119 male) were analyzed. Hazard of death was higher in the TACE versus HDR brachytherapy group (HR, 4.04; P < .001). Median estimated PFS was 32.8 months (95% CI: 12.5, 58.7) in the HDR brachytherapy group and 11.6 months (95% CI: 4.9, 22.7) in the TACE group. Hazard of disease progression was higher in the TACE versus HDR brachytherapy group (HR, 2.23; P < .001). Conclusion In selected treatment-naive patients with unresectable HCC, treatment with CT-guided HDR brachytherapy led to improved OS and PFS compared with TACE. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Chapiro in this issue.

Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis.

BACKGROUND: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America. OBJECTIVES: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America. METHODS: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers. RESULTS: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text. CONCLUSIONS: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Modelling evolutionary tempo and mode using formal morphological spaces and Markov chain principles.

Evolutionary tempo and mode summarize ancient and controversial subjects of theoretical biology such as gradualism, convergence, contingence, trends, and entrenchment. We employed an integrative methodological approach to explore the evolutionary tempo and mode of Lepidosaurian phalangeal formulae (PFs). This approach involves quantifying the frequencies of morphological changes along an evolutionary trajectory. The five meristic characters encoded by PFs are particularly valuable in revealing evolutionary patterns, owing to their discrete nature and extensive documentation in the literature. Based on a pre-existing dataset of PFs from 649 taxa (35 Lepidosauria families, including fossils), from which there exists a unique repertoire of 53 formulations, our approach simultaneously considers phenetic and phylogenetic data. This culminates in a diagram accounting for the phylogenetic dynamic of evolution traversing across different regions of morphospace. The method involves enumerating phenotypical options, reconstructing phenotypes across the phylogeny, projecting phenotypes onto a morphospace, and constructing a flow network from the frequency of evolutionary transitions between unique phenotypic conditions. This approach links Markovian chains and evolutionary trajectories to formally define parameters that describe the underlying transitions of morphological change. Among other results, we found that (a) PF evolution exhibits a clear trend towards reduction in the phalangeal count and that (b) evolutionary change tends to occur significantly between morphologically similar PFs. Notwithstanding, although minor but not trivial, transitions between distant formulas -jumps- occur. Our results support a pluralistic view including stasis, gradualism, and saltationism discriminating their prevalence in a target character evolution.

Towards reproducible radiomics research: introduction of a database for radiomics studies.

OBJECTIVES: To investigate the model-, code-, and data-sharing practices in the current radiomics research landscape and to introduce a radiomics research database. METHODS: A total of 1254 articles published between January 1, 2021, and December 31, 2022, in leading radiology journals (European Radiology, European Journal of Radiology, Radiology, Radiology: Artificial Intelligence, Radiology: Cardiothoracic Imaging, Radiology: Imaging Cancer) were retrospectively screened, and 257 original research articles were included in this study. The categorical variables were compared using Fisher's exact tests or chi-square test and numerical variables using Student's t test with relation to the year of publication. RESULTS: Half of the articles (128 of 257) shared the model by either including the final model formula or reporting the coefficients of selected radiomics features. A total of 73 (28%) models were validated on an external independent dataset. Only 16 (6%) articles shared the data or used publicly available open datasets. Similarly, only 20 (7%) of the articles shared the code. A total of 7 (3%) articles both shared code and data. All collected data in this study is presented in a radiomics research database (RadBase) and could be accessed at https://github.com/EuSoMII/RadBase . CONCLUSION: According to the results of this study, the majority of published radiomics models were not technically reproducible since they shared neither model nor code and data. There is still room for improvement in carrying out reproducible and open research in the field of radiomics. CLINICAL RELEVANCE STATEMENT: To date, the reproducibility of radiomics research and open science practices within the radiomics research community are still very low. Ensuring reproducible radiomics research with model-, code-, and data-sharing practices will facilitate faster clinical translation. KEY POINTS: • There is a discrepancy between the number of published radiomics papers and the clinical implementation of these published radiomics models. • The main obstacle to clinical implementation is the lack of model-, code-, and data-sharing practices. • In order to translate radiomics research into clinical practice, the radiomics research community should adopt open science practices.

Reproducibility of radiomics quality score: an intra- and inter-rater reliability study.

OBJECTIVES: To investigate the intra- and inter-rater reliability of the total radiomics quality score (RQS) and the reproducibility of individual RQS items' score in a large multireader study. METHODS: Nine raters with different backgrounds were randomly assigned to three groups based on their proficiency with RQS utilization: Groups 1 and 2 represented the inter-rater reliability groups with or without prior training in RQS, respectively; group 3 represented the intra-rater reliability group. Thirty-three original research papers on radiomics were evaluated by raters of groups 1 and 2. Of the 33 papers, 17 were evaluated twice with an interval of 1 month by raters of group 3. Intraclass coefficient (ICC) for continuous variables, and Fleiss' and Cohen's kappa (k) statistics for categorical variables were used. RESULTS: The inter-rater reliability was poor to moderate for total RQS (ICC 0.30-055, p < 0.001) and very low to good for item's reproducibility (k - 0.12 to 0.75) within groups 1 and 2 for both inexperienced and experienced raters. The intra-rater reliability for total RQS was moderate for the less experienced rater (ICC 0.522, p = 0.009), whereas experienced raters showed excellent intra-rater reliability (ICC 0.91-0.99, p < 0.001) between the first and second read. Intra-rater reliability on RQS items' score reproducibility was higher and most of the items had moderate to good intra-rater reliability (k - 0.40 to 1). CONCLUSIONS: Reproducibility of the total RQS and the score of individual RQS items is low. There is a need for a robust and reproducible assessment method to assess the quality of radiomics research. CLINICAL RELEVANCE STATEMENT: There is a need for reproducible scoring systems to improve quality of radiomics research and consecutively close the translational gap between research and clinical implementation. KEY POINTS: • Radiomics quality score has been widely used for the evaluation of radiomics studies. • Although the intra-rater reliability was moderate to excellent, intra- and inter-rater reliability of total score and point-by-point scores were low with radiomics quality score. • A robust, easy-to-use scoring system is needed for the evaluation of radiomics research.

Granulomatous meningoencephalitis and blindness associated with Mycobacterium tuberculosis complex infection in a senile female chimpanzee (Pan troglodytes).

A 40-year old female chimpanzee (Pan troglodytes) developed hyporexia, weight loss, followed by progressive and complete blindness. Tomography demonstrated an intracranial mass in the rostroventral brain involving the optic chiasm, with a presumptive diagnosis of neoplasm. However, histopathology revealed a granulomatous meningoencephalitis, and tissue samples tested positive for Mycobacterium tuberculosis.

Molecular detection of Sarcocystis sp. in a kept under human care black capuchin monkey (Sapajus nigritus., Goldfuss 1809) with necrotizing encephalitis.

A senile male black capuchin monkey (Sapajus nigritus) kept under human care in a Zoo was found dead after 2 weeks presenting signals of weight loss and hyporexia. Histopathological revealed a necrotizing encephalitis. Although it was not observed microscopically, Sarcocystis sp infection was detected in brain tissue from molecular assays. These infections have been rarely described in neotropical primates, particularly associated with tissue lesions.

Dermatologic Fungal Neglected Tropical Diseases-Part I. Epidemiology and Clinical Features.

In this part 1 of a 2-part continuing medical education series, the epidemiology, clinical features, and diagnostic methods for fungal skin neglected tropical diseases (NTDs), which include eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis, are reviewed. These infections, several of which are officially designated as NTDs by the World Health Organization (WHO), cause substantial morbidity and stigma worldwide and are receiving increased attention due to the potential for climate change-related geographic expansion. Domestic incidence may be increasing in the setting of global travel and immunosuppression. United States dermatologists may play a central role in early detection and initiation of appropriate treatment, leading to decreased morbidity and mortality.

Dermatologic Fungal Neglected Tropical Diseases-Part II. Management and Morbidity.

In this part 2 of a 2-part continuing medical education series, the management, outcomes, and morbidities for fungal skin neglected tropical diseases (NTDs), including eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis are reviewed. While fungal skin NTDs are associated with poverty in resource-limited settings, they are more often associated with immunosuppression and global migration in the United States. These infections have a high morbidity burden, including disfigurement, physical disability, coinfection, malignant transformation, mental health issues, and financial impact. For most fungal skin NTDs, management is difficult and associated with low cure rates. Dermatologists play a central role in initiating appropriate treatment early in disease course in order to improve patient outcomes.

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.

While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.

Does Dual-Energy Computed Tomography Material Decomposition Improve Radiomics Capability to Predict Survival in Head and Neck Squamous Cell Carcinoma Patients? A Preliminary Investigation.

OBJECTIVE: Our study objective was to explore the additional value of dual-energy CT (DECT) material decomposition for squamous cell carcinoma of the head and neck (SCCHN) survival prognostication. METHODS: A group of 50 SCCHN patients (male, 37; female, 13; mean age, 63.6 ± 10.82 years) with baseline head and neck DECT between September 2014 and August 2020 were retrospectively included. Primary tumors were segmented, radiomics features were extracted, and DECT material decomposition was performed. We used independent train and validation datasets with cross-validation and 100 independent iterations to identify prognostic signatures applying elastic net (EN) and random survival forest (RSF). Features were ranked and intercorrelated according to their prognostic importance. We benchmarked the models against clinical parameters. Intraclass correlation coefficients were used to analyze the interreader variation. RESULTS: The exclusively radiomics-trained models achieved similar ( P = 0.947) prognostic performance of area under the curve (AUC) = 0.784 (95% confidence interval [CI], 0.775-0.812) (EN) and AUC = 0.785 (95% CI, 0.759-0.812) (RSF). The additional application of DECT material decomposition did not improve the model's performance (EN, P = 0.594; RSF, P = 0.198). In the clinical benchmark, the top averaged AUC value of 0.643 (95% CI, 0.611-0.675) was inferior to the quantitative imaging-biomarker models ( P < 0.001). A combined imaging and clinical model did not improve the imaging-based models ( P > 0.101). Shape features revealed high prognostic importance. CONCLUSIONS: Radiomics AI applications may be used for SCCHN survival prognostication, but the spectral information of DECT material decomposition did not improve the model's performance in our preliminary investigation.

Comparison of 96-kV and 120-kV cone-beam CT for the assessment of cochlear implants.

BACKGROUND: To compare the diagnostic value of 120-kV with conventional 96-kV Cone-Beam CT (CBCT) of the temporal bone after cochlear implant (CI) surgery. METHODS: This retrospective study included CBCT scans after CI surgery between 06/17 and 01/18. CBCT allowed examinations with 96-kV or 120-kV; other parameters were the same. Two radiologists independently evaluated following criteria on 5-point Likert scales: osseous spiral lamina, inner and outer cochlear wall, semi-circular canals, mastoid trabecular structure, overall image quality, metal and motion artefacts, depiction of intracochlear electrode position and visualisation of single electrode contacts. Effective radiation dose was assessed. RESULTS: Seventy-five patients (females, n = 39 [52.0%], mean age, 55.8 ± 16.5 years) were scanned with 96-kV (n = 32, 42.7%) and 120-kV (n = 43, 57.3%) protocols including CI models from three vendors (vendor A n = 7; vendor B n = 43; vendor C n = 25). Overall image quality, depiction of anatomical structures, and electrode position were rated significantly better in 120-kV images compared to 96-kV (all p < = 0.018). Anatomical structures and electrode position were rated significantly better in 120-kV CBCT for CI models from vendor A and C, while 120-kV did not provide improved image quality in CI models from vendor B. Radiation doses were significantly higher for 120-kV scans compared to 96-kV (0.15 vs. 0.08 mSv, p < 0.001). CONCLUSIONS: 120-kV and 96-kV CBCT provide good diagnostic images for the postoperative CI evaluation. While 120-kV showed improved depiction of temporal bone and CI electrode position compared to 96-kV in most CI models, the 120-kV protocol should be chosen wisely due to a substantially higher radiation exposure.

Clinical factors associated with systemic sporotrichosis in Brazil.

BACKGROUND: Systemic sporotrichosis occurs when organs, other than subcutaneous tissues and lymph nodes, are infected. Interestingly, systemic sporotrichosis in apparently immunocompetent individuals is increasing in Brazil, but data on clinical manifestations and risk factors are scarce. Most of the existing data on such condition relate to people living with HIV. We aimed to study the risk factors associated with systemic sporotrichosis among HIV-negative and HIV-positive patients. METHODS: We performed a retrospective cross-sectional study with 80 patients from Brazil, diagnosed between 2014 and 2021. The association between disease classification, clinical presentation and risk factors were analysed by logistic regression. RESULTS: Of the 80 patients, 29 (36.3%) presented with systemic sporotrichosis. All HIV-positive patients developed the systemic form, with increased mortality (p = .002). Alcohol ingestion (p = .009) and diabetes (p = .010) were associated with systemic disease. Alcohol ingestion seemed to favour pulmonary infection (p = .013) and, diabetes favoured osteoarticular (p = .009) and ocular involvement (p = .033). The occurrence of fever (p = .001) and weight loss (p = .006) were significantly associated with systemic sporotrichosis, while meningeal involvement (p = .001) increased mortality risk. Nine (11.3%) patients died from sporotrichosis. The presence of fungal structures in the mycological examination of the patients' lesions were associated with the systemic form (p = .017) and death (p = .002). CONCLUSION: Our study points to the factors that drive systemic sporotrichosis other than HIV, such as alcohol ingestion and diabetes. Considering the high number of patients presenting severe sporotrichosis, the recognising these factors may contribute to timely diagnosis and proper treatment.

Natural history and prognostic factors of candidemia in kidney transplant recipients: A retrospective, multinational study.

BACKGROUND: The natural history of candidemia in kidney transplant recipients (KTR) remains poorly understood. This study aimed to evaluate mortality, prognostic factors and overall graft loss after candidemia in KTRs. METHODS: This is a retrospective multicentre study enrolling all KTRs ≥15 years old with candidemia diagnosed at hospitals in Brazil, Spain and Italy from 2010 to 2020. Primary endpoints were mortality rates at 14 and 30 days. Secondary endpoints were prognostic factors of 14-day mortality and overall graft loss. RESULTS: We enrolled 93 KTRs of which 75 were from Brazil. The mean time interval from transplantation to the onset of candidemia was 45.2 ± 61.5 months. 42% of all patients were on haemodialysis, 31.3% had an episode of sepsis and 39% underwent surgery within 30 days before fungemia. European patients were more likely to receive echinocandin (32 vs. 72%, p < .001). 22.7% of Brazilian patients did not receive any antifungal before death. All-cause mortality at 14 days was higher in Brazil (41.3 vs. 11.1%, p = .016). Candida colonisation (OR 6.91 [95% CI: 1.08-44.3], p = .042) and hypotension (OR 4.87 [95% CI: 1.62-14.66], p = .005) were associated with 14-day mortality. Echinocandin treatment had a protective effect (OR 0.19 [95% CI: 0.05-0.73], p = .015). Graft loss at 90 days occurred in 48% of patients (70.7 in Brazil vs. 22.2% in Europe, p < .01). CONCLUSIONS: Candidemia in KTR is usually documented late after engraftment in patients requiring HD, surgical procedures and dysbiosis secondary to antibiotic use. Mortality was higher in Brazil. Echinocandin therapy was associated with improved survival.

Genetic parameters and genome-wide association studies for mozzarella and milk production traits, lactation length, and lactation persistency in Murrah buffaloes.

Genetic and genomic analyses of longitudinal traits related to milk production efficiency are paramount for optimizing water buffaloes breeding schemes. Therefore, this study aimed to (1) compare single-trait random regression models under a single-step genomic BLUP setting based on alternative covariance functions (i.e., Wood, Wilmink, and Ali and Schaeffer) to describe milk (MY), fat (FY), protein (PY), and mozzarella (MZY) yields, fat-to-protein ratio (FPR), somatic cell score (SCS), lactation length (LL), and lactation persistency (LP) in Murrah dairy buffaloes (Bubalus bubalis); (2) combine the best functions for each trait under a multiple-trait framework; (3) estimate time-dependent SNP effects for all the studied longitudinal traits; and (4) identify the most likely candidate genes associated with the traits. A total of 323,140 test-day records from the first lactation of 4,588 Murrah buffaloes were made available for the study. The model included the average curve of the population nested within herd-year-season of calving, systematic effects of number of milkings per day, and age at first calving as linear and quadratic covariates, and additive genetic, permanent environment, and residual as random effects. The Wood model had the best goodness of fit based on the deviance information criterion and posterior model probabilities for all traits. Moderate heritabilities were estimated over time for most traits (0.30 ± 0.02 for MY; 0.26 ± 0.03 for FY; 0.45 ± 0.04 for PY; 0.28 ± 0.05 for MZY; 0.13 ± 0.02 for FPR; and 0.15 ± 0.03 for SCS). The heritability estimates for LP ranged from 0.38 ± 0.02 to 0.65 ± 0.03 depending on the trait definition used. Similarly, heritabilities estimated for LL ranged from 0.10 ± 0.01 to 0.14 ± 0.03. The genetic correlation estimates across days in milk (DIM) for all traits ranged from -0.06 (186-215 DIM for MY-SCS) to 0.78 (66-95 DIM for PY-MZY). The SNP effects calculated for the random regression model coefficients were used to estimate the SNP effects throughout the lactation curve (from 5 to 305 d). Numerous relevant genomic regions and candidate genes were identified for all traits, confirming their polygenic nature. The candidate genes identified contribute to a better understanding of the genetic background of milk-related traits in Murrah buffaloes and reinforce the value of incorporating genomic information in their breeding programs.

Unveiling Trichosporon austroamericanum sp. nov.: A Novel Emerging Opportunistic Basidiomycetous Yeast Species.

During an epidemiological survey, a potential novel species within the basidiomycetous yeast genus Trichosporon was observed. The clinical strain was obtained from a urine sample taken from a Brazilian kidney transplant recipient. The strain was molecularly identified using the intergenic spacer (IGS1) ribosomal DNA locus and a subsequent phylogenetic analysis showed that multiple strains that were previously reported by other studies shared an identical IGS1-genotype most closely related to that of Trichosporon inkin. However, none of these studies provided an in-depth characterization of the involved strains to describe it as a new taxon. Here, we present the novel clinically relevant yeast for which we propose the name Trichosporon austroamericanum sp. nov. (holotype CBS H-24937). T. austroamericanum can be distinguished from other siblings in the genus Trichosporon using morphological, physiological, and phylogenetic characters.

Genomic analysis of genotype-environment interaction in age at first calving of Murrah buffaloes.

Age at first calving (AFC) is a measure of sexual maturity associated with the start of productive life of dairy animals. Additionally, a lower AFC reduces the generation interval and early culling of females. However, AFC has low heritability, making it a trait highly influenced by environmental factors. In this scenario, one way to improve the reproductive performance of buffalo cows is to select robust animals according to estimated breeding value (EBV) using models that include genotype-environment interaction (GEI) with the application of reaction norm models (RNMs). This can be achieved by understanding the genomic basis related to GEI of AFC. Thus, in this study, we aimed to predict EBV considering GEI via the RNM and identify candidate genes related to this component in dairy buffaloes through genome-wide association studies (GWAS). We used 1795 AFC records from three Murrah buffalo herds and formed environmental gradients (EGs) from contemporary group solutions obtained from genetic analysis of 270-day cumulative milk yield. Heritability estimates ranged from 0.15 to 0.39 along the EG. GWAS of the RNM slope parameter identified important genomic regions. The genomic window that explained the highest percentage of genetic variance of the slope (0.67%) was located on BBU1. After functional analysis, five candidate genes were detected, involved in two biological processes. The results suggested the existence of a GEI for AFC in Murrah buffaloes, with reclassification of animals when different environmental conditions were considered. The inclusion of genomic information increased the accuracy of breeding values for the intercept and slope of the reaction norm. GWAS analysis suggested that important genes associated with the AFC reaction norm slope were possibly also involved in biological processes related to lipid metabolism and immunity.

Kisspeptin-10 Improves Testicular Redox Status but Does Not Alter the Unfolded Protein Response (UPR) That Is Downregulated by Hypothyroidism in a Rat Model.

Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control (n = 15), Hypo (n = 13) and Hypo + Kp10 (n = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of Sod1, Sod2 and Gpx1, as well as the expression of Grp78, Atf6, Ho1 and Chop. Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction.

Developing, Purchasing, Implementing and Monitoring AI Tools in Radiology: Practical Considerations. A Multi-Society Statement From the ACR, CAR, ESR, RANZCR & RSNA.

Artificial Intelligence (AI) carries the potential for unprecedented disruption in radiology, with possible positive and negative consequences. The integration of AI in radiology holds the potential to revolutionize healthcare practices by advancing diagnosis, quantification, and management of multiple medical conditions. Nevertheless, the ever­growing availability of AI tools in radiology highlights an increasing need to critically evaluate claims for its utility and to differentiate safe product offerings from potentially harmful, or fundamentally unhelpful ones. This multi­society paper, presenting the views of Radiology Societies in the USA, Canada, Europe, Australia, and New Zealand, defines the potential practical problems and ethical issues surrounding the incorporation of AI into radiological practice. In addition to delineating the main points of concern that developers, regulators, and purchasers of AI tools should consider prior to their introduction into clinical practice, this statement also suggests methods to monitor their stability and safety in clinical use, and their suitability for possible autonomous function. This statement is intended to serve as a useful summary of the practical issues which should be considered by all parties involved in the development of radiology AI resources, and their implementation as clinical tools.