RÉSUMÉ
The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1-TPDS1) and a neurodevelopmental disorder known as Kury-Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype-phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.
Sujet(s)
Études d'associations génétiques , Prédisposition génétique à une maladie , Mutation germinale , Protéines suppresseurs de tumeurs , Ubiquitin thiolesterase , Humains , Mutation germinale/génétique , Ubiquitin thiolesterase/génétique , Protéines suppresseurs de tumeurs/génétique , Phénotype , Conseil génétique , Syndromes néoplasiques héréditaires/génétique , Troubles du développement neurologique/génétique , Protéine BRCA1/génétique , FemelleRÉSUMÉ
Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
Sujet(s)
Maladie d'Alzheimer , Apolipoprotéine E4 , Gouttelettes lipidiques , Microglie , Animaux , Femelle , Humains , Mâle , Souris , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Peptides bêta-amyloïdes/métabolisme , Apolipoprotéine E4/génétique , Apolipoprotéine E4/métabolisme , Cellules souches pluripotentes induites/cytologie , Gouttelettes lipidiques/métabolisme , Gouttelettes lipidiques/anatomopathologie , Microglie/cytologie , Microglie/métabolisme , Microglie/anatomopathologie , Triglycéride , Protéines tau , Milieux de culture conditionnés , Phosphorylation , Prédisposition génétique à une maladieRÉSUMÉ
Background and Objective: Malignant pleural mesothelioma (MPM) is a very aggressive primary tumor of the pleura whose main risk factor is exposure to asbestos. However, only a minority of exposed people develops MPM and the incidence of MPM cases without an apparent association with asbestos exposure has been increasing in recent years, suggesting that genetic predisposing factors may play a crucial role. In addition, several studies reported familial cases of MPM, suggesting that heredity may be an important and underestimated feature in MPM development. Several candidate genes have been associated with a predisposition to MPM and most of them play a role in DNA repair mechanisms: overall, approximately 20% of MPM cases may be related to genetic predisposition. A particular category of patients with high susceptibility to MPM is represented by carriers of pathogenic variants in the BAP1 gene. Germline variants in BAP1 predispose to the development of MPM following an autosomal dominant pattern of inheritance in the familial cases. MPMs in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. In the present narrative review, we presented a comprehensive overview of genetic susceptibility in the development of MPM. Methods: The narrative review is based on a selective literature carried out in PubMed in 2023. Inclusion criteria were original articles in English language, and clinical trials (randomized, prospective, or retrospective). Key Content and Findings: We summarized the somatic and germline variants and the differences in terms of clinicopathological features and prognosis between gene-related MPM (GR-MPM) and asbestos-related MPM (AR-MPM). We also discussed the indications for screening, genetic testing, and surveillance of patients with BAP1 germline variants. Conclusions: In this narrative review, we have emphasized that the BAP1 gene's harmful germline variations are inherited in an autosomal dominant manner in familial cases. MPMs in individuals with these variations are less severe, and their medical care necessitates a collaborative effort. Additionally, we have outlined the current therapeutic prospects for MPM, including the possibility of gene-specific therapy, which is currently promising but still requires clinical validation.
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Working memory refers to the temporary retention of a small amount of information used in the execution of a cognitive task. Working memory impairments are one of the common hallmarks of many neuropsychiatric and neurological disorders including schizophrenia and Alzheimer's disease. Here, we investigated Fischer 344 and Long-Evans rats for strain and sex differences in working memory using the operant-based DNMTP task. Rats were required to press one of two levers presented during a sample phase and followed by a 2-32 second delay, the rats were then required to press the opposite, nonmatch, lever during the choice phase. We found a transient strain difference with Fischer 344 rats performing better than Long-Evans early in training. The Fischer 344 strain showed stable performance across sessions while the performance of Long-Evans increased in the later sessions. Since different background rat strains are used for transgenic rat models, it is critical to be able to compare the behavioral performance across different strains. These findings have implications in behavioral neuroscience research as understanding the typical behavioral endpoints in different background strains will aid our understanding of how different models affect behavioral performance.
Sujet(s)
Recherche comportementale , Mémoire à court terme , Femelle , Mâle , Rats , Animaux , Rat Long-Evans , Caractères sexuelsRÉSUMÉ
Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aß (fAß) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
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Animals must modify their behavior based on updated expected outcomes in a changing environment. Prelimbic cortex (PrL) neural encoding during learning predicts, and is necessary for, appropriately altering behavior based on a new expected outcome value following devaluation. We aimed to determine how PrL neural activity encodes reward predictive cues after the expected outcome value of those cues is decreased following conditioned taste aversion. In one post-devaluation session, rats were tested under extinction to determine their ability to alter their behavior to the expected outcome values (i.e., extinction test). In a second post-devaluation session, rats were tested with the newly devalued outcome delivered so that the rats experienced the updated outcome value within the session (i.e., re-exposure test). We found that PrL neural encoding of the cue associated with the devalued reward predicted the ability of rats to suppress behavior in the extinction test session, but not in the re-exposure test session. While all rats were able to successfully devalue the outcome during conditioned taste aversion, a subset of rats continued to consume the devalued outcome in the re-exposure test session. We found differential patterns of PrL neural encoding in the population of rats that did not avoid the devalued outcome during the re-exposure test compared to the rats that successfully avoided the devalued outcome. Our findings suggest that PrL neural encoding dynamically tracks expected outcome values, and differential neural encoding in the PrL to reward predictive cues following expected outcome value changes may contribute to distinct behavioral phenotypes.
Sujet(s)
Conditionnement classique , Récompense , Animaux , Cortex cérébral , Signaux , Extinction (psychologie) , RatsRÉSUMÉ
OBJECTIVE: To quantify the radial and lateral extents of femoral cam lesions in FAI patients relative to the alpha angle and correlate with clinical data. METHODS: Retrospective study of 81 hips with femoral cam morphology that underwent arthroscopic surgery between 2017 and 2019. At each hour over the clockface, the alpha angle (α) (abnormal defined as > 55°), radial extent, and lateral extent of cam lesions were measured on CT. These measurements were correlated with clinical and arthroscopic data. Statistics included independent samples t-test and chi-squared test with Bonferroni correction and multivariate logistic regression. RESULTS: Larger α at 12:00-4:00 in males vs females (56.6-63.4° vs 44.3-58.5°, P < 0.001) and at 2:00-4:00 with elite sports participation vs without (56.7-70.9° vs 49.6-61.1°, P ≤ 0.004). Independent risk factors for radial extent beyond 12:00-3:00 were: male sex (OR 4.82, 95% CI [1.46, 15.85], P = 0.010), BMI > 25 (OR 4.74, 95% CI [1.61, 14.00], P = 0.005), and elite sports participation (OR 3.28, 95% CI [1.09, 9.82], P = 0.034). Lateral extent increased at 1:00-4:00 in males vs females (7.8-18.6 mm vs 1.6-9.1 mm, P < 0.0001). A 16% prevalence of distal cam lesions was found at locations with normal α, resulting in underestimation of radial extent by an average of 1.7 hours. CONCLUSION: There is a positive correlation between the alpha angle, lateral extent, and radial extent of cam lesions. FAI patients who were male, participated in elite level sports, and had a BMI > 25 had larger cam lesions. A larger alpha angle is a risk factor for cartilage damage. Patients may have distal cam lesions at locations with normal alpha angles, though their significance is unknown.
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Conflit fémoro-acétabulaire , Femelle , Conflit fémoro-acétabulaire/imagerie diagnostique , Conflit fémoro-acétabulaire/anatomopathologie , Conflit fémoro-acétabulaire/chirurgie , Fémur/anatomopathologie , Articulation de la hanche/anatomopathologie , Articulation de la hanche/chirurgie , Humains , Mâle , Études rétrospectivesRÉSUMÉ
Four patients, from three families, with alkaptonuria receiving 4-hydroxyphenylpyruvate dioxygenase-inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton-pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton-pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.
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ABSTRACT: Acral CD8(+) lymphoma is a provisional entity in the latest edition of the WHO Lymphoma Classification and is associated with a highly specific dot-like pattern of immunohistochemical expression of CD68. We report a case of an ulcerated solitary cutaneous lesion arising on the forehead of an adult man, which had a CD8(+) cytotoxic phenotype and areas of dot-like CD68 positivity, but with a number of features that significantly detracted from the classically described acral CD8(+) lymphoma. The nosological status of the lesion is discussed with respect to a preferred diagnosis of peripheral T-cell lymphoma, not otherwise specified.
Sujet(s)
Lymphocytes T CD8+/anatomopathologie , Tumeurs de la tête et du cou/anatomopathologie , Lymphome T cutané/anatomopathologie , Cuir chevelu , Tumeurs cutanées/anatomopathologie , Sujet âgé de 80 ans ou plus , Humains , Immunohistochimie , Lymphome T cutané/classification , Mâle , Phénotype , Tumeurs cutanées/classificationRÉSUMÉ
BACKGROUND: To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes. METHODS: A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction. RESULTS: Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner. CONCLUSIONS: We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders.
Sujet(s)
Cocaïne , Animaux , Encéphale , Comportement de recherche de substances , Mâle , Noyau accumbens , Cortex préfrontal , Rats , Rat Long-EvansRÉSUMÉ
BACKGROUND: Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression. METHODS: Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA. RESULTS: There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined ochronosis semiquantitative scoring showed an increase between V-1 and V0 (P < .01), followed by a decrease at V1, V2, and V3, in the VAR group (P < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease (P < .05). CONCLUSIONS: Nitisinone decreases HGA and partially reverses ochronosis.
RÉSUMÉ
BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.
Sujet(s)
Alcaptonurie/traitement médicamenteux , Alcaptonurie/métabolisme , Cyclohexanones/administration et posologie , Antienzymes/administration et posologie , Internationalité , Nitro-benzoates/administration et posologie , Adulte , Sujet âgé , Alcaptonurie/diagnostic , Calendrier d'administration des médicaments , Femelle , Acide homogentisique/métabolisme , Humains , Études longitudinales , Mâle , Adulte d'âge moyen , Méthode en simple aveugle , Résultat thérapeutiqueRÉSUMÉ
OBJECTIVE: To describe institutional clinical policies and individual provider opinions regarding aneuploid embryo transfer (aET). DESIGN: A survey about clinical policies was electronically sent to Society for Assisted Reproductive Technology (SART) member laboratory directors, and a separate survey about personal opinions was electronically sent to all SART members. SETTING: Not applicable. PATIENTS: Patients pursuing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Current clinical policies about aET were described. Individual provider opinions about aET in the context of specific aneuploidies and mosaicism were also described. RESULTS: A total of 48 laboratory directors and 212 individual providers responded to their respective surveys. Twelve (25%) clinics report that they do not have a policy regarding aET, but clinics performing PGT-A in >100 cycles per year were more likely to have a policy. Half of the individual providers agree that an embryo with trisomy 21 should be available for aET, but most disagreed with aET of embryos with other aneuploidies and most were either unsure about or unwilling to transfer embryos with mosaicism. Those who worked in primarily patient-facing roles held more agreeable opinions regarding aET. CONCLUSION: There is no consensus regarding ideal clinical policies for aET. The wide range of current clinical practices and individual provider opinions regarding under what circumstances, if any, aET should be available to patients indicates that this is a divisive issue among ART providers, and there is a clear need for specific professional guidelines to address this issue.
Sujet(s)
Aneuploïdie , Transfert d'embryon/normes , Cliniques de fertilité/normes , Politique de santé , Types de pratiques des médecins/normes , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Transfert d'embryon/méthodes , Expertise , Femelle , Cliniques de fertilité/statistiques et données numériques , Dépistage génétique/méthodes , Dépistage génétique/normes , Humains , Nouveau-né , Mâle , Adulte d'âge moyen , Mosaïcisme/embryologie , Types de pratiques des médecins/statistiques et données numériques , Grossesse , Diagnostic préimplantatoire/méthodes , Diagnostic préimplantatoire/normes , Enquêtes et questionnaires , États-UnisSujet(s)
Dapsone/usage thérapeutique , Vascularite leucocytoclasique cutanée/anatomopathologie , Ponction-biopsie à l'aiguille , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Maladies rares , Indice de gravité de la maladie , Résultat thérapeutique , Vascularite leucocytoclasique cutanée/diagnosticSujet(s)
Dapsone/usage thérapeutique , Vascularite leucocytoclasique cutanée/traitement médicamenteux , Vascularite leucocytoclasique cutanée/anatomopathologie , Ponction-biopsie à l'aiguille , Humains , Immunohistochimie , Dermatoses de la jambe/diagnostic , Dermatoses de la jambe/étiologie , Mâle , Adulte d'âge moyen , Maladies rares , Indice de gravité de la maladie , Résultat thérapeutique , Vascularite leucocytoclasique cutanée/diagnosticRÉSUMÉ
BACKGROUND: Professional autonomy is a key concept in understanding nurses' roles in delivering patient care. Recent research exploring the role of autonomy in the nursing work environment indicated that English and American nurses had differing perceptions of autonomy. This qualitative study aimed to explore the understanding and experiences of autonomy of nurses working in England. METHODS: A descriptive phenomenological analysis of data from 48 semi-structured interviews with registered nurses from two National Health Service (NHS) hospitals (purposive sample) was used to explore the concept of autonomy. RESULTS: Six themes were identified: working independently; working in a team; having professional skills and knowledge; involvement in autonomy; boundaries around autonomy; and developing autonomy requires support. A key finding was that nurses related autonomy to their clinical work and to the immediate work environment of their ward, rather than to a wider professional context. Nurses also perceived that autonomy could be turned off and on rather than comprising an integrated aspect of nursing. CONCLUSIONS: Findings suggest that nurses in England, as framed by the sample, had a local ward-focused view of autonomy in comparison to nurses in America, who were reported to relate autonomy to a wider involvement in hospital level committees. Findings further indicate that autonomy was practiced occasionally, rather than incorporated into practice. Findings highlight the need for nurses in England to adopt a broader perspective and actively contribute to writing hospital guidelines and policies that recognise the importance of autonomy to nurse training and practice.
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Osteochondrosis is an abnormality of the epiphyses or epiphyseal equivalents (round bones and apophyses) during later stages of endochondral ossification. This process of abnormal endochondral ossification can occur at various locations throughout the body. The pathogenesis of osteochondrosis is under active investigation. In humans, the process of abnormal endochondral ossification has been attributed to a combination of vascular insult and trauma. Although the proposed etiology of osteochondrosis varies based on body part affected, the overall process is defined by necrosis, revascularization and repair. As such, common radiologic findings include those of osseous destruction and associated inflammation. The purpose of this review is to discuss the current understanding of osteochondroses as a disease entity and explore imaging features of osteochondroses throughout the body.
Sujet(s)
Imagerie par résonance magnétique/méthodes , Ostéochondrose/imagerie diagnostique , Radiographie/méthodes , Épiphyses (os)/imagerie diagnostique , HumainsRÉSUMÉ
AIM: To report a qualitative study of themes Registered Nurses raised spontaneously about their work environment, in a cross-sectional survey study when responding to the Essentials of Magnetism II (EOMII) scale. DESIGN: Qualitative descriptive survey. METHODS: At the end of the EOMII scale, a free form text section was included asking nurses to add comments about their ward/work environment. Of the 247 nurses who completed the EOMII scale, 30% (N = 75) provided comments. Inductive content analysis was used to analyse the textual information generated. RESULTS: Three key themes emerged: "nurses need nurses to nurse"; working as a team and workplace environment. Participants described issues they were facing which comprised high turnover rates, inadequate staffing levels, increasing workload and high stress levels. Particular attention was drawn to the role of the ward manager in promoting a positive work environment, good teamwork and quality patient care.
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OBJECTIVE. The purpose of this study is to evaluate the global trend in artificial intelligence (AI)-based research productivity involving radiology and its subspecialty disciplines. CONCLUSION. The United States is the global leader in AI radiology publication productivity, accounting for almost half of total radiology AI output. Other countries have increased their productivity. Notably, China has increased its productivity exponentially to close to 20% of all AI publications. The top three most productive radiology subspecialties were neuroradiology, body and chest, and nuclear medicine.