Takayasu Arteritis (TAK) is a rare large vessel vasculitis affecting the aorta and its major branches. The heterogeneous and often severe clinical manifestations result from systemic and local inflammation as well as end-organ ischemia. Disease flares are common and contribute to accrued damage over time with significant morbidity and mortality. Newer understanding of the pathogenesis in TAK has paved the way for the use of pathway targeting agents such as tumor necrosis factor (TNF)α- or interleuking (IL)-6-inhibitors with improved disease control. Nevertheless, long-term data are lacking, particularly in children; prognosis often remains guarded and the disease burden high. This article aims at providing a comprehensive review of childhood-onset TAK with a focus on recent publications. Takayasu Arteritis (TAK) is the most common large vessel vasculitis in children. It is characterized by granulomatous inflammation of the aorta, its major branches and the pulmonary arteries that may result in segmental stenosis, occlusion, dilatation and/or aneurysms. Systemic inflammation, local inflammatory processes and organ dysfunction secondary to ischemia lead to a highly variable clinical presentation and significant morbidity if untreated. Therapy is often extrapolated from adult studies given the very low prevalence of the disease in children. Better understanding of pathophysiologic mechanisms has resulted in the use of cytokine targeting therapies. Although early recognition and therapy seem to improve outcome in childhood-onset TAK, long-term follow-up data are lacking and prognosis remains guarded. This article reviews recent publications on epidemiology, pathogenesis, clinical presentation, laboratory biomarkers, imaging, treatment, and outcomes with a focus on the pediatric literature.The incidence and prevalence of TAK are much higher in adults compared to children. A recent systematic review and meta-analysis found an incidence rate of 1.11 per million person-years  with considerable variation across different populations .Epidemiological data in childhood-onset TAK are scarce. The annual incidence rate reported in a Swedish study was 0.4  per million for childhood-onset TAK . The preTakayasu Arteritis most commonly affects young women with a peak incidence between 20 and 40 years of age. It is unknown why TAK occurs predominantly in women. In children, female preponderance is lower than in adult-onset TAK and estimated around 2.5:1–3:1 –9.While there are still major gaps in our understanding, the etiology of TAK has begun to be elucidated. Current knowledge of pathophysiology is mostly extrapolated from adult studies and animal models of large vessel vasculitis . Both, tMultiple proinflammatory cytokines have been implicated in the pathogenesis of TAK . IncreasT cells, and particularly Th1 and Th17 responses seem to play an important role in driving the systemic and vascular manifestations in TAK, as demonstrated by increased expression of Th1 and Th17-related cytokines in patients with TAK that correlate with disease activity  pathway in T cell activation and the development of vascular lesions in TAK. mTOR is a kinase that drives different signaling pathways to regulate cell differentiation, proliferation and metabolism , as wellammation , 24. Thuammation .in vitro  signaling pathway in the pathophysiology of TAK. This was first shown in a large vessel vasculitis mouse-model, in which the JAK1/3 inhibitor tofacitinib significantly reduced vessel wall infiltrates and expression of IFNγ, IL-17, and IL-21, and further diminished angiogenesis and hyperplasia of the intima . Using tin vitro . The samin vitro . In summThe involvement of humoral immune mechanisms has previously been demonstrated by the presence of circulating anti-endothelial cell antibodies , autoantIL12B, IL6, RPS9/LILRB3, and FCGR2A/FCGR3A, which represent potential targets in pathophysiology and treatment of TAK , particularly in regions with a high prevalence of tuberculosis infection, there is not enough evidence to establish a causal relationship . A possiTo summarize, almost all arms of the immune response, from cellular components of both the innate and adaptive immune systems to downstream humoral mediators and their signaling components, have been implicated in the pathogenesis of TAK, pointing to the complexity of the immune reaction. It remains to be elucidated, what is causation and what association.The diagnosis of childhood-onset TAK is based on clinical criteria and angiographic abnormalities, and is supported by laboratory findings. It requires a high index of suspicion, especially in children, because (1) onset is often insidious with non-specific symptoms mimicking many inflammatory conditions, (2) the clinical presentation greatly varies due to variable localization and extent of the vessels involved, and (3) the occurrence is rare.Different sets of classification criteria have been proposed for childhood-onset TAK. The initial 1990 American College of Rheumatology (ACR) classification criteria for TAK were based on data from adult patients with TAK . In 2005Disease often presents with non-specific constitutional symptoms, including fever and systemic inflammation (pre-pulseless stage), and evolves to vascular symptoms attributable to occlusive arteritis. Up to 25% of children are diagnosed during the late inactive, “burnt-out” phase of the disease, where symptoms result from irreversible vascular damage rather than active vasculitis lesions –46. TAK In children, the aorta  is most commonly affected, followed by the renal, subclavian, carotid, and splanchnic arteries . StenotiOrgan-specific manifestations result from ischemia secondary to vascular stenosis. Arterial hypertension is the main presenting feature  and is primarily related to renal artery stenosis and subsequent renovascular hypertension , 58. ArtMore recently, several groups have been directly comparing pediatric and adult TAK cohorts , 60–62. Duration of symptoms before treatment initiation has been positively associated with disease extent and damage . DiseaseAlthough various biomarkers have been explored for monitoring disease activity in TAK, none has yet been identified for reliable use in clinical practice. In children, elevation of acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) is commonly observed , 55, butAmong inflammatory molecules, IL-6, a pro-inflammatory cytokine that drives CRP synthesis and thrombocytosis and increases ESR seems promising as a biomarker and a treatment target. In tocilizumab-treated patients with TAK, longitudinal IL-6 monitoring might be useful for assessing disease activity and for detecting infections. While infections seem to trigger a significant, but short-term peak in serum IL-6, persistent IL-6 elevation may indicate subclinical disease activity or relapse , 74.Further, IL-6 independent inflammatory biomarkers, such as S100 proteins or pentraxin-3 are being investigated . Pentrax18F-FDG-PET). Although listed in the EULAR/PRINTO/PReS classification criteria for childhood-onset TAK, conventional angiography is nowadays rarely used and restricted to very few, specific indications such as angiographic imaging prior to revascularization procedures  angiography, computer tomography (CT) angiography, Doppler ultrasound (US), and fluorodeoxyglucose positron emission tomography (PET)  reliably detect signs suggestive of vascular inflammation and allow diagnosis of TAK even in the early pre-stenotic phase, their role for follow-up monitoring is less evident. As an example, vascular changes such as vessel wall thickening or 18F-FDG uptake are not specific to active TAK, but may also be induced by healing processes or fibrotic remodeling. This causes difficulties for interpretation of imaging as there is no clear correlation of imaging results with disease activity during the course of disease. Hence, it is crucial to combine clinical, laboratory and imaging evaluation for disease management.While these imaging modalities  and vasculitides secondary to systemic lupus erythematosus, spondylarthritis or sarcoidosis. Non-inflammatory diseases such as aortic coarctation, Williams syndrome, Marfan or Ehlers-Danlos syndrome, and fibromuscular dysplasia (FMD) may mimic childhood-onset TAK. In contrast to TAK, FMD is not an inflammatory disease; but it may be difficult to differentiate from TAK during the “burned-out” disease phase as–unlike in adults–the characteristic angiographic “string of beads” pattern is rarely observed in childhood-onset FMD .Because of progressive or relapsing disease most children with TAK require immunosuppressive therapy to control systemic and vascular inflammation. Challenges in clinical management include the timely treatment initiation and assessment of disease activity to guide therapeutic decision-making. Diagnostic delay can result in irreversible vascular damage even prior to diagnosis and assessment of treatment response is difficult, because reliable laboratory and radiological biomarkers for disease activity are lacking.Treatment recommendations are extrapolated from adult TAK studies, as high-level evidence including randomized controlled trials is not available to guide treatment in childhood-onset TAK. To date, high-dose corticosteroids remain the mainstay for induction of remission , 88, altBetter understanding of disease pathophysiology has resulted in the use of cytokine- and pathway-targeting agents such as TNFα-, IL-6, and more recently JAK-inhibitors , 16, 27.For TNFα-inhibitors, evidence is mainly extrapolated from adults. The largest cohort study retrospectively included 209 adults with TAK and compared efficacy of TNFα-inhibitors (63% of patients) and the IL-6 inhibitor tocilizumab (37% of patients) . Efficacn = 10 treatment episodes) or tocilizumab (n = 2 treatment episodes). Biologic agents were associated with significantly better 2-year flare-free survival rates and greater likelihood to reach inactive disease at last follow-up compared with conventional DMARDs or corticosteroids alone  with corticosteroids and methotrexate (n = 26 adults with TAK) (p = 0.02), lower relapse rates  and significantly lower average corticosteroid doses during the study period compared to those on methotrexate. Treatments were well tolerated with a good safety profile  have been published to date with promising results , 114–121IL12B as a susceptibility gene for TAK in genome-wide association studies  has been validated in children. Other disease activity measurement tools such as the ITAS 2010 and ITAS-A, which additionally includes acute phase reactants, have been developed specifically for TAK, but are only validated in adults.The US National Institute of Health (NIH) criteria, commonly used to assess disease activity in TAK, define active disease as the presence of constitutional symptoms, new bruits, increased acute phase reactants or new angiographic findings .Although tools for assessment of disease damage exist for adults with TAK, none has been validated in children. These scores may help to assess accumulated damage over time, but discrimination between disease and treatment-related damage may be difficult .Children with TAK present with more systemic inflammation and more widespread vascular disease than adults. However, relapses and accrued damage are high and equally frequent in both groups and seem to be associated with longer duration of symptoms , 52, 61.Recent advances in disease recognition and therapeutic strategies have decreased morbidity and mortality in TAK. Several recent studies have reported the benefit of biologic therapies such as TNFα-inhibitors or Tocilizumab in adults, with up to 80% of patients achieving complete remission at 6 months , 112. InYoung age and high CRP at disease onset, stroke, lower BMI, longer duration of symptoms and high accrued damage scores have been associated with poor outcomes including increased mortality in childhood-onset TAK , 46, 52.Timely diagnosis of childhood-onset TAK is important because the disease is associated with a significant morbidity and mortality. Despite persisting gaps in the knowledge of the pathophysiology of TAK, critical inflammatory pathways contributing to the disease begin to be elucidated and provide avenues for new treatment approaches. Treatment recommendations are mostly based on adult TAK studies with level of evidence two or three, although few randomized controlled trials have been published with biologic agents. Corticosteroids remain the mainstay for induction of remission, but biologic agents such as TNFα- or IL-6- and JAK-inhibitors are increasingly used, particularly in severe, relapsing or DMARD-refractory cases. Whether upfront use of biologic agents improve long-term outcome, yet needs to be investigated.Large international collaborative efforts are required to conduct well-designed studies to determine efficacy of current therapeutic regimens, to identify reliable biomarkers that help to assess disease activity and guide treatment choice, and to better define the long-term outcome of pediatric TAK using validated pediatric outcome measures. One of the main goals is thereby finding therapeutic strategies to reduce cumulative corticosteroid use and to achieve the best possible efficiency-tolerance balance with minimal cumulative damage.FA reviewed the literature and drafted the manuscript. RY and RL reviewed the literature and revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Moreover, the combination of 68Ga-labeled PSMA-based PET imaging and radiotherapy using PSMA radioligand therapy (RLT) becomes a novel treatment option for CRPC patients. The existing studies have demonstrated this therapeutic strategy as an effective and well-tolerated therapy among CRPC patients. PSMA-based PET imaging can accurately detect CRPC lesions and describe their molecular features with quantitative parameters, which can be used to select the best choice of treatments, monitor the response, and predict the outcome of RLT. This review discussed the current and potential role of PSMA‐based imaging and RLT in the diagnosis, treatment, and prediction of prognosis of CRPC.Castration-resistant prostate cancer (CRPC) is a therapy-resistant and lethal form of prostate cancer as well as a therapeutic challenge. Prostate-specific membrane antigen (PSMA) has been proved as a promising molecular target for optimizing the theranostics for CRPC patients. When combined with PSMA radiotracers, novel molecular imaging techniques such as positron emission tomography (PET) can provide more accurate and expedient identification of metastases when compared with conventional imaging techniques. Based on the PSMA-based PET scans, the accurate visualization of local and  Prostate cancer (PCa) has 1.3 million new cases each year worldwide, making it the second most prevalent cancer among men . Since HThe diagnosis of CRPC depends on the occurrence of biochemical and/or radiological progression in a castration environment (castrate serum testosterone < 50 ng/dl or 1.7 nmol/l). At present, conventional imaging modalities (CIMs), such as magnetic resonance imaging (MRI), abdominopelvic computed tomography (CT), and whole-body bone scans (BS) are still recommended as the standard imaging techniques to evaluate radiological progression. However, CIMs may delay the diagnosis of CRPC due to the lack of accuracy in identifying metastases, therefore postponing the necessary therapy switch. More powerful imaging tools are needed to identify CRPC earlier and timely to trigger subsequent treatments.Over the last decades, chemotherapeutic drugs, such as cabazitaxel and docetaxel, second-generation inhibitors of the androgen-receptor signaling, such as enzalutamide and abiraterone acetate, as well as radium-223 have improved the clinical benefits of patients with CRPC. However, as the disease progresses, these treatments eventually become useless. Furthermore, the lack of reliable markers to well predict the outcome of CRPC patients remains a challenge in the management of CRPC patients.In the last two decades, PSMA (a 750–amino acid type II transmembrane glycoprotein) has been demonstrated as a potential diagnostic and therapeutic target for PCa . It has 68Ga-PSMA-11 . Therefore, PET/CT that combines the molecular advantages of PET and morphologic features of CT is superior to the CIMs for the diagnosis and monitoring of various cancer types including PCa. Moreover, when combined with PSMA radiotracers, PET/CT showed remarkable sensitivity and specificity in the field of PCa . Of late-PSMA-11  and 18F-F-DCFPyL  as novel225Ac) and Lutetium-177 (177Lu), respectively, can be used to label PSMA ligands. 18F-FDG) PET/CT have been proven to be predictive of the outcome of patients before receiving RLT, thereby improving the selection of the best choice of management option and drug at an individual level.Radioligand therapy (RLT), targeting the PSMA, showed desired antitumor effects by combining the therapeutic radionuclides with the PSMA ligands and delivering a high-radiation dose to the targeted tumor cells . Alpha- CRPC has always been a bottleneck for PCa, which calls for continuous exploration. Based on the current research, the emergence of PSMA-based PET scans and RLT has brought hope to tackle the problems in the diagnostic, therapeutic, and prognostic field of CRPC. This review aims to discuss the current role of PSMA‐based imaging and RLT in CRPC.The biochemical progression and/or radiological progression of PCa with castrated serum testosterone < 50 ng/dl or 1.7 nmol/l refer to as CRPC. CRPC can be divided into metastatic CRPC (mCRPC) and nonmetastatic CRPC (nmCRPC) according to the distant metastasis state based on the reports of CIMs. The biochemical progression is defined as three consecutive increases in the prostate-specific antigen (PSA), which results in a two-time 50% increase from the baseline PSA level, reaching > 2 ng/ml  or PSA >The conventional imaging techniques, such as CT and MRI, have a limited accuracy to detect metastatic PCa lesions in lymph nodes and bones. In a pooled analysis of 18 clinical studies, CT showed a limited sensitivity [42% (95% CI 26–56%)] for the detection of metastatic lymph nodes . Due to In 2019, Frendler et al. employed the PSMA-based PET to evaluate tumor burden in 200 patients who were diagnosed as nmCRPC via CIMs. However, based on the reevaluation of PSMA-based PET scans, 55% showed evidence of distant metastases (M1 stage) leading to a stage migration from nmCRPC to mCRPC . LikewisAt present, the shift from hormone-sensitive prostate cancer (HSPC) to CRPC is diagnosed based on the PSA progression and radiological progression evaluated by CIMs according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) . In consThe higher sensitivity of PSMA-based PET when compared with the CIMs caused the earlier detection of metastases among the PCa patients, leading to a stage transition from nmCRPC to mCRPC in almost half of the patients . After t223Ra-dichloride therapy is eligible only for patients with two or more bone metastases but without known visceral metastases based on cross-sectional imaging techniques, as reported in the ALSYMPCA trial  of metastatic (M1) sites . In theo68Ga-PSMA-11-based PET/CT-guided radiotherapy for the treatment of 23 oligometastatic PCa patients, including nine mCRPC patients. A total of 83% of patients showed remission after a 7-month median follow-up . The 177Lu-PSMA-617 also showed a more significant delay in the radiographic as well as PSA progression. However, the median PFS between the two groups was similar  and OS (15.3 months vs. 11.3 months) after a median follow-up of 20.9 months (In the first prospective single-arm Phase 2 study (LuPSMA), herapies . The ranreatment . When co similar . In addi9 months .177Lu was combined with the PSMA imaging and therapeutic ligand (PSMA I&T), showing similar PSMA affinity, dosimetry, and pharmacokinetics to those of 177Lu-PSMA-617   . Several177Lu is the most clinically used radiation source for RLT. However, not all the patients responded to 177Lu-labeled PSMA ligands, and the presence of diffuse bone marrow infiltration was still considered a health risk for the hematologically toxic effects despite the overall low toxicity of 177Lu ; 78.6% of the patients showed a 50% decrease in the PSA levels by the end of the follow-up period , stopping the 225Ac-RLT in 10–25% of the patients. Sialendoscopy with dilatation, steroid injection, saline irrigation, salivary gland cooling externally using ice packs, and intraparenchymal botulinum toxin injections were performed with limited success. Therefore, the reduction of salivary toxicity needs further investigations . BiTE therapies generally involve a bispecific antibody with two binding sites which target the tumor-associated antigen on tumor cells, besides cluster of differentiation 3 (CD3) on T cells. In doing so, it induces T-cell activation, cytokine production, and T-cell–mediated lysis leading to targeted tumor cell death. PSMA is the perfect candidate antigen for BiTE therapies due to its advantages as described above . The firPSMA-RLT is an emerging treatment option for patients with mCRPC. The identification of patients at risk of poor prognosis is clinically important. Although widely used, the relative changes in conventional imaging and laboratory parameters (mainly serum PSA levels) might not be associated with treatment response or patient outcome. The PSMA-based PET/CT has been widely used to select patients for PSMA-RLT , and parameters derived from PET/CT scans have been demonstrated to be related to patients’ outcomes receiving PSMA-RLT (31–33).in vivo. SUV derived from PSMA-PET/CT could represent tumor PSMA expression and therefore be used to predict responses and clinical outcomes. Ferdinandus et al. examined the patients, who were recruited in the LuPSMA trial, to investigate if their baseline imaging had any predictive value. The average intensity of PSMA-avid tumor uptake was significantly correlated with the OS, using a threshold value of SUV of >3  is a widely used quantifiable parameter in PET scans and partially reflects the tracer expression UV of >3 . They prUV of >3 . VlachosUV of >3 . Two expUV of >3 , dose adUV of >3 .Apart from routinely used parameters like SUV, radiomic methods are regarded as efficient, and reliable methods to extract a variety of quantitative features from imaging data. It has been proven to be useful to identify the curative effect and predict outcomes in cancers, such as breast carcinoma . At presA potential response to the PSMA-RLT is predicated based on the elevated PSMA expression. In general, the PSMA expression in PCa lesions increases with tumor dedifferentiation and castration resistance. However, dedifferentiated neuroendocrine PCa may be an exception in which PSMA expression can be low due to the suppression of the PSMA gene . TherefoIt has been demonstrated that the glucose metabolism of PCa correlated with the cell proliferative activity expressed by the Ki-67 index. This supported the assumption that PCa with higher glucose metabolism might progress rapidly with a poorer prognosis . Suman eAn assessment of 50 Lu-PSMA trial patients to use both the FDG and PSMA-PET revealed that the patients with limited levels of FDG uptake in disease had a longer OS . It was 177Lu-PSMA-617-RLT. This retrospective study included 29 patients with mCRPC continuously receiving PSMA-RLT, who underwent both the PSMA and FDG PET/CT scans at the time of the disease progression. In the consolidated PET imaging, 17/29 patients had at least one mismatch metastasis (FDG+/PSMA−) and showed a significantly lower OS of 3.3 months from the time of PET imaging when compared with those without mismatch metastasis. The patients with a higher metabolic tumor volume  had a significantly shorter OS than the patients with a lower MTV while analyzing the subgroup of the patients with mismatch findings  during ongoing findings . Michalsfindings .p = 0.807) and four cycles (p = 0.442), which might be due to the small sample size. Therefore, the prognosis value of dynamic observation with dual tracer PET/CT is needed to be evaluated in a larger cohort (Hartrampf et al. tried to evaluate the potential prognostic value of newly found FDG+/PSMA− lesions during the PSMA-RLT. A total of 32 patients, having no FDG+/PSMA− before RLT, underwent the dual tracer PET/CT imaging after two or four cycles of PSMA-RLT. There were no significant differences in the OS among the patients with and without FDG+/PSMA− lesions after two cycles (r cohort .Dual tracer PET/CT of FDG and PSMA allow for the whole-body characterization of the PCa phenotype, which has been beneficial. First, they recognize the tumor sites, which are FDG-positive but PSMA-negative, indicating that they are not susceptible to PSMA-RLT. Second, the combination of FDG and PSMA tracers gives a whole-body scan rather than being limited to the osseous metastasis only. Third, they offer a unique estimation of tumor glycolysis, which is enhanced in the aggressive subtypes of the tumor. It was speculated that in the mCRPC, the tumor cells lose their PSMA expression and glucose reprogrammed with the disease progression, thereby making it more aggressive. Tumors with reduced PSMA uptake and high FDG uptake are aggressive disease sites, which cannot be successfully targeted by PSMA-RLT. From a theoretical perspective, the patients with PSMA-avidity and high FDG-avidity lesions might be more eligible for taxane-based chemotherapies rather than the PSMA-RLT. However, the patients, lacking such lesions, are likely to show a better response to PSMA-RLT and second-generation antiandrogens, which could be considered early in the course of the disease . How the18F-FDG the PSMA-based imaging can serve as a prognostic tool for mCRPC patients before receiving PSMA-RLT. Radiomic analyses of PSMA-PET scans in CRPC patients are also worthy of more exploration.PSMA-based PET/CT imagings have a higher sensitivity and specificity than conventional imaging techniques, which have the potential to redefine the nmCRPC and mCRPC. PSMA-based PET/CT may serve as a complementary or even independent biomarker of CRPC tumor load. Further studies are needed to elucidate the accuracy and clinical benefits of PSMA-based imagings in CRPC patients. Owing to the accurate location of CRPC lesions, the PSMA-PET can serve as a guide for MDT in patients with oligometastatic CRPC. The PSMA ligands labeled with various alpha or beta emitters radionuclides have a comparative or even better survival benefit than conventional third‐line therapies for mCRPC. However, there is a need to explore strategies to attain deeper and more durable responses. Nonradioactive approaches like BiTE therapies are also of emerging interest. In combination with other radiotracers, such as


Besides, the probability of having condylar bony changes was positively correlated with the number of psychological problems concomitantly present in an adult . The intraobserver agreement value for CBCT analysis was substantial (κ = 0.732). Conclusions: This study found that positive PHQ-15 (somatization) and GAD-7 (anxiety) scores were associated with condylar bony changes in adults. Moreover, the number of psychological problems concomitantly present in an adult was positively associated with the probability of having condylar bony changes.Background: This article studies the association between psychological status and condylar bony changes in adults and assesses psychological questionnaires as an indicator of potential condylar bony changes. It is meaningful because condylar bony changes, a severe subtype of TMD and big concern in orthodontic treatment, would likely be ignored in patients with few TMD symptoms, in which case, even with potential psychological problems  being noticed, orthodontists may underestimate the possibility or severity of condylar bony changes and thus may not perform relevant examinations. Methods: A total of 195 adults  who consulted orthodontists and had clinical records were included in this study. Initial CBCT images taken before orthodontic treatment were used for observing their condylar bony changes, and a comprehensive questionnaire conducted by each adult to evaluate psychological status was collected. Age, sex, TMD symptom history, scores on Patient Health Questionnaire-9 (PHQ-9), PHQ-15 and Generalized Anxiety Disorder-7 (GAD-7), and condylar bony changes of these adults were recorded. Odds ratios (OR) and 95% confidence intervals (CIs) for identifying the independent risk factors associated with condylar bony changes were calculated with univariate and multivariate logistic regression analysis. The kappa statistic was used to assess intraobserver reliability of CBCT analysis. Results: The scores of PHQ-15 (OR: 2.088, 95% CI: 1.061–4.108,  Temporomandibular disorders (TMDs) are a heterogenous group of disorders including pain-related musculoskeletal disorders and painless function disturbances . TMD hasHowever, the correlation between psychological status and condylar bony changes, one of the most severe subtypes of TMD, has not been sufficiently studied. To specify and prove the degree of their association is important for the reason that condylar bony changes, as a big risk in orthodontic treatment, would likely be ignored since it is not necessarily accompanied by pain ,8,9. ForThere is a wealth of self-administered questionnaires that can be used to assess psychological status, among which the most widely used are the 9-item version of the Patient Health Questionnaire (PHQ-9), 15-item version of the Patient Health Questionnaire (PHQ-15), and 7-item version of the Generalized Anxiety Disorder (GAD-7) . The PHQFor the examination of bone-related diseases, cone-beam computed tomography (CBCT) is now widely used in dentistry for its unique advantage in three-dimensional (3D) imaging . AlthougThe aim of this study was to explore the association between the psychological status and condylar bony changes in adults by matching the survey assessment of mental health-related questionnaires and CBCT findings.This was a retrospective survey-based study. Potential adult patients who had had orthodontic consultations in the Department of Orthodontics, West China Hospital of Stomatology, Sichuan University  from June 2018 to June 2022 were filtered in this study. Before orthodontic treatment, they were asked to take a CBCT examination and complete a comprehensively questionnaire that contained their basic information, TMD symptom history, and assessment using the PHQ-9, PHQ-15 and GAD-7. Those adults were filtered manually and selected as research samples based on the following inclusion and exclusion criteria.The inclusion criteria were: (1) older than 18 years; (2) CBCT images were taken within 1 week before or after completing the questionnaire; (3) the imaging field of CBCT should three-dimensionally cover the whole structures of bilateral mandibular condyles; (4) no history of craniofacial syndrome or systemic disease.The exclusion criteria were: (1) not all items of the questionnaire were finished; (2) insufficient quality of CBCT images, (3) history of immune disease, severe bone defects, or orthognathic surgery.All the CBCT images were taken with the same CBCT machine , which was set according to the manufacturers’ recommendations . The voxel size was 125 μm. The CBCT data were stored in DICOM multifile format.Before assessment, the DICOM data were imported into Dolphin software  and the head positions were three-dimensionally reoriented with the Frankfort plane parallel to the ground. Then, the CBCT images without participant information were analyzed blindly under identical conditions. After a two-week interval, CBCT images were blindly analyzed by the same operator for the second time. The differences between the two analyses were marked out and discussed with an expert to confirm the results. According to previous research ,24, the Articular surface flattening in a young population indicates potential condylar resorption while the cortical margin is still intact . It is nThe questionnaires were analyzed on each item. Variables were classified into categorical and continuous types. The categorical variables in the questionnaire included sex and TMD symptom history and were then converted into continuous variables. Sex was scored as 0  and 1 . TMD symptom history was scored as 0 (no symptoms ever) and 1 (symptom history including TMJ clicking and pain). The continuous variables included age and scores on the PHQ-9, PHQ-15, and GAD-7. According to the definition, the thresholds to be defined as a positive PHQ-9 score for depression, a positive PHQ-15 score for somatization, and a positive GAD-7 score for anxiety were 5. Further, the number of the psychological problems concomitantly present in a participant was defined in values (0–3), as shown in t tests were used to test the difference in age between the divided groups of participants . The sociodemographic characteristics of the participants were analyzed using the t test or chi-squared test. The kappa statistic was used to assess intraobserver reliability for CBCT analysis. The relationships between degree of condylar bony changes and potential risk factors, including sex, age, TMD symptom history, PHQ-9, PHQ-15, and GAD-7 scores and number of psychological problems concomitantly present in a participant, were evaluated using univariate and multivariate logistic regression analysis. Multicollinearity among potential risk factors correlated with condylar bony changes were estimated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for risk factors. The threshold of statistical significance was set at 0.05.Based on the Kendall rule and events per variable (EPV) theory , the theA total of 195 adults  met the inclusion and exclusion criteria and were selected as research samples. Ages ranged from 18 to 54 years old; and the average age was 26.44 ± 6.68 years. No significant differences were found between females and males in terms of age.According to the results of CBCT analysis and questionnaires, 128 participants (65.64%) were considered to have bilateral normal condyles (degree = 0), and 67 participants (34.36%) were considered to have condylar bony deformation (degree = 1). The intraobserver agreement value for CBCT analysis of condylar bony changes was substantial (κ = 0.732). No statistically significant differences in age were found between these two groups .The PHQ-9, PHQ-15 and GAD-7 scores were analyzed, and we found that 42.05% of all the participants had at least one psychological problem. The numbers and percentages of participants with depression, somatization, and anxiety are listed in p < 0.05). The proportion of participants with concomitant psychological problems was higher in the group with condylar bony changes than the group without condylar bony changes.Baseline characteristics of participants are shown in To identify the independent risk factors for condylar changes, univariate logistic regression analysis was firstly used and ORs were estimated. The results are shown in p < 0.05), PHQ-15 score  and GAD-7 score  had statistically significant correlations with condylar bony changes. In addition, the number of psychological problems concomitantly present in a participant  was positively associated with the probability of having condylar bony changes.TMD symptom history  of age, sex and TMD symptom history were below 2, which indicated the absence of multicollinearity. The VIFs of the PHQ-9, PHQ-15 and GAD-7 scores were above 2 and below 5, which indicated moderate multicollinearity and were within acceptable level. The VIF of number of psychological problems concomitantly present in a participant was above 10, which indicated high multicollinearity and was considered problematic ; hence, Then, the above three risk factors with statistical significance  were set as the dependent factors. Univariate logistic regression analysis was used again to figure out the potential confounding variables based on other risk factors .The results indicated that no confounding variable was statistically related to TMD symptom history. For PHQ-15 and GAD-7 scores, age, sex and TMD symptom history were not confounding variables. However, PHQ-9, PHQ-15 and GAD-7 scores were significantly correlated with each other. Therefore, these three psychological risk factors were seen as the confounding variables to each other and removed when assessing the association between condylar bony change and PHQ-15 and GAD-7 scores in the following multivariate logistic regression analysis.As we mentioned above, psychological risk factors were confounding variables to each other and removed in the multivariate statistics. Hence, multivariate logistic regression analysis was conducted twice to respectively estimate the ORs and significance of PHQ-15 score and GAD-7 scores associated with the condylar bony change, as shown in p < 0.05), PHQ-15 score  and GAD-7 score  showed statistically significant correlations with condylar bony changes.TMD symptom history  and GAD-7  was positively correlated with condylar bony changes, which means positive scores on the PHQ-15 and GAD-7 indicate a possibility of condylar changes. Moreover, the number of psychological problems concomitantly present in an adult is positively associated with the probability of condylar bony changes . Compared with previous research that proved a close association between psychological status and TMDs, this study innovatively combined a questionnaire survey and CBCT images and further revealed the correlation between psychological status and condylar bony changes in adults. A similar phenomenon between psychological problems and condylar bony changes was seen in some animal experiments that used classic animal models of anxiety and stress. To be specific, Jiao K et al. established a mouse model of chronic immobilization stress by placing mice in a ventilated 50 mL laboratory conical tube for 4 h daily for generating endogenous psychological stress, and found that such psychological stress promoted condylar subchondral bone loss and cartilage degradation [Our study aimed to explore the association between psychological status and condylar bony changes in adults. A comprehensive questionnaire was used to evaluate the psychological status of these adults when they consulted orthodontists. Condylar bony changes were examined using CBCT images. The results indicated that psychological status assessed with the PHQ-15 . This can be easily understood. TMD symptom history reported by patients themselves may reflect preexisting TMDs. Without removal of pathogenic factors or timely treatment, TMDs may result in TMJ osteoarthritis (OA) and even cause condylar bony deformation, which can be easily observed with CBCT images [Condylar bony changes also had an association with TMD symptom history . As previous studies have shown, the relationship of depression, somatization and anxiety is a kind of comorbidity and can be called the “SAD” triad [This study also indicated that PHQ-9, PHQ-15, and GAD-7 scores were confounding variables to each other  was associated with condylar bony changes in adults having orthodontic consultations. The number of the psychological problems  concomitantly present in an adult is positively associated with the probability of having condylar bony changes. It indicated that screening for potential psychological problems using the PHQ-9, PHQ-15 and GAD-7 could be potentially useful for detecting condylar bony changes before orthodontic diagnosis and treatment of adults; vice versa, when condylar bony changes are detected, special attention should be given to the patients’ psychological condition throughout future treatment. Future studies are needed to validate the relationship between psychological status and condylar bony changes.


A higher 30-day mortality has been observed in patients with first-presentation ST elevation myocardial infarction (STEMI) who have no standard modifiable cardiovascular risk factors (SMuRFs), i. e., diabetes, hypertension, hyperlipidemia, and current smoker. In this study, we evaluate the clinical outcomes and CMR imaging characteristics of patients with and without SMuRFs who presented with first-presentation STEMI.Patients from the Third DANish Study of Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI-3) with first-presentation STEMI were classified into those with no SMuRFs vs. those with at least one SMuRF.p < 0.001) with more males , more likely to have left anterior descending artery (LAD) as the culprit artery , and poor pre-PCI (percutaneous coronary intervention) TIMI  flow ≤1 . There was no difference in all-cause mortality, non-fatal reinfarction, or hospitalization for heart failure at 30 days or at long-term follow-up. CMR imaging was performed on 726 patients. SMuRFless patients had larger acute infarct size  and a smaller myocardial salvage index . These differences were attenuated when the higher LAD predominance and/or TIMI 0-1 flow were included in the model.We identified 2,046 patients; 283 (14%) SMuRFless and 1,763 (86%) had >0 SMuRF. SMuRFless patients were older  and NCT01960933 (DANAMI 3-PRIMULTI). Despite the common perception that coronary artery disease (CAD) is well understood and managed, it remains the leading cause of mortality in adults worldwide . Major aA number of large observational studies have shown, somewhat unexpectedly, that SMuRFless STEMI patients have higher in-hospital and 30-day mortality rates after myocardial infarction compared to patients with at least one of the major risk factors –9. A recCardiac magnetic resonance (CMR) imaging allows direct quantitation of the area at risk (AAR), myocardial infarct size, and MVO. Both myocardial infarct size and MVO are associated with poor outcome –12. CMR The Third DANish Study of Optimal Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI-3) trial programme  consisted of three randomized controlled STEMI trials performed at four large primary percutaneous coronary intervention (PCI) centers in Denmark between March 2011 and February 2014 –20. The A subgroup of DANAMI-3 patients recruited at one center  had CMR performed according to a standard protocol to evaluate the effects of randomizations on a surrogate marker. This CMR-subgroup provided an optimal opportunity to examine any potential differences in CMR variables such as AAR, infarct size, MVO, and LV remodeling between individuals with no SMuRFs vs. those with at least one SMuRF. Patients were included in the sub-study if they had baseline and/or follow-up CMR performed .The CMR protocol has been described in detail previously . Brieflyt-test  or Mann–Whitney U test . Mean ± SD or median  or percentages are reported. Changes in baseline to follow-up CMR measures were assessed using the paired t-test. Categorical variables were compared using Pearson's chi-squared or Fisher's exact test as appropriate. Multivariable linear regression analyses were performed using SMuRFless patients as a predictor for final infarct size or final MSI adjusting for pre-specified clinically relevant variables: male sex, age, ECG–to-wire time, former smoking, thrombolysis in myocardial infarction (TIMI) flow 0–1 pre-PCI and culprit left anterior descending artery (LAD). A Cox proportional hazards regression model was used to assess the individual risk of a clinical outcome in SMuRFless patients. Finally, an additional logistic regression model was performed to determine the independent predictors of TIMI 0-1 flow, adjusting for pre-specified clinically relevant variables, namely, male sex, age, symptom to wire time, multivessel disease, culprit LAD, heart rate, systolic blood pressure,  and those with at least one SMuRF. Continuous variables were compared using Student's ressure,  and SMuRA total of 2,217 patients were included in the DANAMI-3 trial program. After excluding 160 patients with previous acute myocardial infarction, PCI, and coronary artery bypass grafting (CABG), and 11 patients with missing SMuRF data, the total study population was comprised of 2,046 patients. Of these, 283 (14%) were SMuRFless and 1,763 (86%) had >0 SMuRFs. A total of 726 (13%) patients underwent baseline and/or follow-up CMR imaging: 688 (95%) had CMR at baseline and 639 (88%) had CMR at follow up. A total of 87 patients had only baseline CMR and 38 had only follow-up CMR performed. Of the 726 patients in the CMR sub-group, 61 (8%) were SMuRFless, and 665 (92%) had >0 SMuRFs .p = 0.45, iPOST p = 0.70, and PRIMULTI p = 0.89).In the CMR subgroup, the proportion of SMuRF-less and SMuRF patients in the three randomized trials was similar . In the The baseline clinical characteristics for the total population and the CMR subgroup are presented in p = 0.001) and the CMR subgroup . In the total study population, the left anterior descending artery (LAD) was the culprit artery in a higher proportion of SMuRFless patients . In the CMR sub-group, the proportion was not significantly different .Procedural characteristics for both populations are presented in Of the 726 patients in the CMR sub-group, 688 (95%) patients had a baseline CMR performed at a median of 0 days [IQR: 0–1] after primary PCI, and 639 (88%) patients had a follow-up CMR performed after a median of 90 days [IQR: 88–96]).p = 0.04) compared to patients with >0 SMuRFs. The increased infarct size to AAR is presented in CMR results are presented in p = 0.03), male sex , p = 0.006), culprit LAD , p = 0.005), and symptom-to-wire time .In a multivariable regression model, the association of SMuRFless status with larger acute infarct size remained significant independent of age, sex, former smoking, and ECG-to-wire time. However, this association was no longer observed if culprit LAD and/or TIMI 0-1 flow pre-PCI were included in the model . As TIMIAt baseline CMR, there was no difference in indexed left ventricle end diastolic volume (LVEDV), indexed left ventricular end systolic volume (LVESV), or left ventricular ejection fraction (LVEF), which were relatively preserved in both groups .p < 0.001 for all). The increase in LVEDV tended to be greater in SMuRF-less participants (p = 0.06). However, this was not significant when indexed for body surface area. The proportion of patients reaching ≥12% increase in LVEDV was equivalent in both groups. All other CMR ventricular remodeling measurements were similar between patients with or without SMuRFs  and AHA (American Heart Association) STEMI guidelines, the proportion of patients with diabetes mellitus, hypertension, hypercholesterolemia, and smoking is a common feature of the baseline characteristics in p < 0.0001) (p = 0.02), however, despite this the incidence of clinical outcomes like all-cause mortality, non-fatal reinfarction, or hospitalization for heart failure at 30 days or long-term follow up was not higher in the SMuRF group. Hence, the presence of higher multivessel disease in the SMuRF group probably did not have an effect on outcomes. The main emphasis of our study was the CMR subgroup to assess CMR imaging features in the two groups. In the CMR subgroup, there was no difference in the presence of multi-vessel disease between SMuRFs and SMuRFless patients .In the recent study of the SWEDEHEART Registry, 30-day mortality rates were ~50% higher in SMuRFless STEMI patients (11.3%) vs. those with at least one modifiable risk factor  . On the The detailed CMR imaging data available enabled us to explore any potential differences in myocardial infarction and remodeling characteristics as a potential explanation of the early mortality. It could be hypothesized that factors involved in heightened susceptibility to coronary artery disease against a background of minimal risk factors may be a reflection of increased inflammatory and pathophysiological signaling downstream of the risk factors. Such signaling may also impact the myocardial response to a myocardial infarction and ischemia-reperfusion injury. However, this hypothesis cannot be confirmed in the present study as SMuRF was not an independent predictor of infarct size and myocardial salvage after adjusting for LAD territory and TIMI 0-1 flow.The most significant predictors of infarct size were a culprit LAD lesion and TIMI 0–1 flow pre-PCI. This is consistent with the established literature, with extensive data demonstrating that STEMI due to LAD as the culprit vessel is associated with larger infarct size, worse left ventricle function, and higher mortality when compared with STEMI due to non-LAD arteries , 29. IntPoor pre-procedural TIMI flow in STEMI patients is associated with larger infarct size, higher fatal arrhythmia events, higher in-hospital, and one-year mortality , 32, 33.CMR is the gold standard for measuring left ventricle volumes and ejection fraction due to its high reproducibility . The DANAlthough three different treatment strategies were used in the three randomized controlled STEMI trials of the DANAMI-3 trial program, there was no difference in clinical outcomes in these trials due to the interventions. Therefore, including patients from three different STEMI trials should not have influenced the clinical outcomes in our study. Furthermore, there was no interaction between the infarct size and either of the treatment arms. The limitations of the study include the low mortality rate and the potential for selection bias of a clinical trial, which contributing to this vs. real-world registries. This must be weighed against the benefits of prospectively collected data in randomized trials, which are less susceptible to missing data than registries. Many comparisons were made leading to the risk of type 1 error. Finally, many patients were lost to CMR, and it is well known that patients suitable for CMR are at lower risk compared to the CMR drop-outs.SMuRFless patients had a larger infarct size and smaller MSI following first-presentation STEMI, but this association was mediated by a higher proportion of LAD-territory events and pre-PCI TIMI 0-1 flow. Despite of this observation, mortality was not significantly different. Whether the finding of LAD territory and flow reduction preponderance in SMuRFless STEMI patients is a chance finding or related to unknown differences in biology remains to be examined.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Third DANish Study of Optimal Acute Treatment of Patients with ST-Segment Elevation Myocardial Infarction (DANAMI-3) trial program  Practitioner Fellowship (GNT1135920) and Center for Research Excellence (GNT1196629), and New South Wales Office of Health and Medical Research (Senior Investigator grant).Author LK reports Speakers honorarium from Novo, Novartis, AstraZeneca and Bohringer, unrelated to this manuscript. TE reports personal fees from Abbott, Bayer, and AstraZeneca outside the submitted work. GF reports personal consulting fees from CSL and grants from Abbott Diagnostic outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities. Theranostics combine diagnostic and therapeutic capabilities into a single pharmaceutical agent; this dual application can be easily achieved after conjugation to radionuclides. The past decade has seen a trend to increased specificity, fastened pharmacokinetics, and personalized medicine. In this review, we discuss the different strategies introduced for the noninvasive detection and treatment of hematological malignancies by radiopharmaceuticals. We also discuss the future applications of these radiotheranostic agents. Hematological malignancies include different heterogeneous malignant conditions, all originating from bone marrow cells or the lymphatic system, resulting from genetic alterations such as translocation, mutation, or gene overexpression . Based o--particle, or Auger electron emitters), while the diagnostic component uses gamma radiation emission that can be detected by a single photon emission computed tomography (SPECT) or positron emission tomography (PET) cameras . This draft circulated among the co-authors, who all provided comments. After three rounds of revisions, all co-authors reviewed and validated the final manuscript.We structured the manuscript into sections: (1) the different components of a theranostic agent, (2) the historical use of mAbs as theranostics, (3) the recent progress and improvements, (4) their applications in hematological malignancies, and (5) future perspectives in their development.For the development of radiolabelled theranostic agents, several variables need to be considered: (i) the selection of an appropriate cell surface target, (ii) selection of a corresponding target-specific binding agent , (iii) the choice of a radionuclide that aligns with the previous two, and finally (iv) a strategy to connect the radionuclide to the binding agent. The structure of these radioconjugates is illustrated in An ideal target antigen for theranostic approaches is highly expressed on the membrane of all tumor cells while absent on normal cells. Such antigens have been identified for some diseases, but not all. The first moieties introduced for specific binding to a well-defined antigen were peptides and mAbs. These mAbs can be isolated from immune or synthetic libraries. The former are obtained after immunization with recombinant proteins or DNA encoding the proteins, taking advantage of the ability of the immune system to generate Ab diversity, while diversity in synthetic repertoires is introduced artificially.The synthetic antibody libraries are constructed with the introduction of genomic diversity at positions most likely to contribute to antigen recognition. Phage display technology is used to identify specific Abs and will create a large antibody repertoire. A number of antibodies can be identified from a single library, to be further expressed and produced in a prokaryotic expression system.mAbs were initially introduced as antigen-binders, but their high molecular weight results in a long serum half-life that facilitates aspecific retention. Antibody engineering techniques allowed the production of smaller antibody fragments and mAb derivatives. Because of their shortened serum half-life and limited off-target retention, they are more and more developed as vectors for Targeted RadioNuclide Therapy (TRNT). On the other hand, Peptide Receptor Radionuclide Therapy (PRRT) combines a cell-targeting peptide similar to the natural circulating ligand, with a therapeutic radionuclide. Well-known examples of PRRT include somatostatin analogues and prostate-specific membrane antigen (PSMA) ligands.via random or site-specific conjugation strategies. In the past, the majority of bioconjugation techniques relied on reactions between bifunctional chelators and amino acids, typically lysines. However, Abs and Ab fragments possess varying numbers of these residues distributed throughout their structure, hampering a tight control of the location and the number of conjugations and finally resulting in poorly-defined and heterogeneous immunoconjugates glycine containing nucleophile . Other evia prosthetic groups, and complexation by using bifunctional chelators are the most used labelling strategies  travel a few millimetres in tissue, after which they undergo annihilation and release two γ-ray photons in opposite trajectories (180° apart). PET scanners utilize the simultaneous detection of these two photons (coincidence detection) to locate the source of the annihilation event. Common radionuclides used for PET imaging are listed in 18F) is widely used in the routine diagnostic imaging of cancers. Its incorporation in 2-deoxy-2-[18F]fluoro-D-glucose allows the detection of most malignancies because of the glucose-analogue structure, which leads to uptake via GLUT1 transporters in cells undergoing glycolytic metabolism. Radioisotopes used in nuclear medicine imaging have short half-lives with low dose ionizing radiation exposure to the patient. However, they are not optimal for long circulating probes, such as the mAbs, that require labelling with long-lived radioisotopes, such as Iodine-124 (124I) or Zirconium-89 (89Zr) physiological processes can be imaged with either PET or SPECT. In PET, positrons  .SPECT scanners on the other hand directly detect the gamma rays emitted by γ-emitters. Unlike PET, a metal parallel-hole collimator is mounted on the flat SPECT detector head to provide photons positional information, and the collimator design has a major impact on the sensitivity and resolution of the system. Coincidence detection in PET technology is significantly more efficient than SPECT at recording events as the collimator, essential for SPECT, results in discarding a high amount of useful emitted photons. Thus, PET provides a much higher sensitivity (2-3 orders of magnitude), quantitation capability and spatial resolution than SPECT. PET sensitivity is further dramatically increased in the next generation total body PET scanners with a long axial field of view (140 cm to 194 cm) .The targeting vector should be matched to an appropriate radionuclide using an applicable conjugation strategy. Should one have an antibody applied, for example, with a longer biological half-life, a radionuclide with a longer half-life would be preferred. The radionuclide must be able to easily combine with the chelator and remain stable over the required period.–, and Auger electrons  , as well as the rate of energy deposition, are all properties with an influence on efficacy . The conrons cfr Table 2.rons cfr . High-LE breaks) . So, hig–emitters in RITs.The growing expertise in radiochemistry and conjugation strategies on the one hand and the increased availability of α-particle emitters on the other, has resulted in the design and production of stable radiolabelled biomolecules . The hig90Y]-ibritumomab tiuxetan  was approved as the first radiolabelled mAb for the treatment of relapsed or refractory low grade B cell non-Hodgkin lymphomas (NHLs)  . Ibritum+ NHL have confirmed the clinical efficacy of 90Y-ibritumomab tiuxetan with superior response rates as compared to rituximab  is another CD20-binding agent composed of tositumomab, a murine anti-CD20 mAb radiolabelled with 131I In patients with chemotherapy‐refractory or transformed low-grade NHL, [131I]-tositumomab resulted in significantly better overall response rates and complete responses as compared to the last chemotherapy regimens  identifying well-defined niches and diseases to treat, and (2) exploring and describing the short and long-term toxicity of TRNT in preclinical and clinical studies.The different applications that we highlight in this article can be found in –particle emitting radionuclide rhenium-188 (188Re) and integrated into the myeloablative treatment before allogeneic SCT for 32 patients with AML or MDS (Hematopoietic stem cell transplantation (SCT) is a treatment option for aggressive hematopoietic malignancies. An autologous SCT consists of a chemotherapeutic conditioning regimen, followed by the administration of the patients’ stem cells to shorten the aplasia. In an allogeneic SCT, the stem cells are derived from an HLA-compatible donor and favor a graft-versus-tumor effect. To increase the efficacy of SCT, RIT protocols are currently being studied to replace high-dose chemotherapy or total body irradiation. The first preliminary studies focused on CD45 and CD66 antigens, expressed by all hematopoietic or myeloid cells, respectively. Anti-CD66 antibodies have been conjugated with the βL or MDS . The bio111In]-labelled mAb BC8 to follow its biodistribution and calculate the internal radiation doses  by injecting the Indium-111 -DOTA-BC8 prior to autologous SCT (with or without chemotherapy)  . Patients absent . The sams absent . Fourtees absent .Some of the toxicities observed with mAb-based RIT are related to the size and prolonged circulation time of mAbs . Indeed,177Lu-Dotatate (Luthatera®), and PSMA ligand, 177Lu-PSMA-617 (Pluvicto®), for neuro-endocrine tumors and prostate cancer therapy, respectively   .Since the large size of mAbs prolongs their clearance, smaller antibody fragments have been introduced in the past decades. Other attractive small proteins are nonimmune scaffold proteins characterized by a simple, highly stable structure as a single chain polypeptide. These scaffold-based binding proteins are small proteins, typically 5–20 kDa, that contain a fixed stable scaffold with variable regions introduced either by varying existing sequences within the scaffold or by longer loop insertions. In this way, libraries can be generated from which specific binders for a defined target protein, protein domain, or modification may be selected. Affibodies have been extensively evaluated for molecular imaging and TNRT. Promising affibody-tracers have been developed for the imaging of molecular targets, such as human epidermal growth factor receptor (HER) 2, epidermal growth factor receptor (EGFR), HER3 and others –41.®) have shown their potential as agents for radionuclide imaging and TRNT. SdAbs are single domain antigen binding fragments, isolated from heavy chain-only Abs that are naturally present in Camelidae  can be more easily and straightforwardly improved by protein engineering when compared to conventional Ab fragments . Their sortase A .in vivo theranostic tracers, using a variety of radionuclides in (non-)clinical studies. The most advanced sdAb under clinical evaluation is a sdAb targeting HER2 that after labelling with 68Ga, identified both primary HER2+ tumors and related metastasis as early as one hour post injection in a phase I study , Astatine-211 (211At) and Bismuth-213 (213Bi)  –62. Cruc (213Bi) .Taken together, both scaffold-based binding protein and sdAbs have the potential to become a new class of theranostic tools in cancer therapy. With their unique properties - easiness in producing, being specifically labelled, small size, high stability, high specificity, and the ability to recognize epitopes that remain undetected by conventional antibodies - sdAbs and scaffold proteins are the ideal vectors to transport cytotoxic radiation to treatment-resistant residual malignant cells.Nanoparticles were initially developed as drug carriers for the delivery of large quantities of pharmaceuticals. They were labelled with radionuclides for studying their pharmacological properties and biodistribution by using SPECT or PET. Nanoparticles have rapidly emerged as radiopharmaceuticals with different applications, including targeted therapy, image-guided therapy and theranostics , 64. Man90Y  .Another way to overcome the potential toxicity of TNRT is to use a two-step, pretargeting procedure in which the targeting agent and radiolabel are injected separately, a concept called pretargeted radioimmunotherapy or PRIT , 70. In Since their introduction in the 1980s, different pretargeting systems have been developed. The first relies on high-affinity interactions between biotin and streptavidin/avidin . Unfortuin vivo . PNA carries a pseudopeptide backbone, composed of repeating N-(2-aminoethyl) glycine units connected by amide bonds.A final strategy for pretargeting is based on the 177Lu-labelled secondary PNA effector probe was evaluated as a therapeutic application , acts as the primary tumor-targeting component and an azide-functionalized effector . The affith PRIT .+ lymphomas  and is currently in clinical trials for relapsed/refractory lymphomas . The therapeutic efficacy of this new radiopharmaceutical has been studied in several preclinical studies. A direct comparison between 177Lu-tetulomab and 177Lu-rituximab showed that 177Lu-tetulomab was more potent in inhibiting cell growth and in improving the survival of lymphoma-bearing mice (177Lu-labeled variant was tested in xenograft models of CLL and NHL (212Pb), that showed a favorable biodistribution and efficacy and prolonged the survival of CLL and NHL xenografted mice with low levels of hematological toxicity  T-cells, and RIT. CD37 is expressed by mature human B cells in the blood and tonsils, but not on T cells, thymocytes, granulocytes, or platelets. Different immunotherapeutic agents, such as mAbs, antibody-drug conjugates, and improved forms of TRNT have been developed in the past years. An anti-CD37 mAb TRNT is developed by Nordic Nanovector ASA as ing mice . Based oing mice . NNV003  and NHL . This chtoxicity .In MM, characterized by an accumulation of malignant plasma cells in bone marrow, the only therapeutic radiopharmaceutical that has entered clinical application so far is the small cyclic pentapeptide pentixafor and its analogue pentixather (binding to the chemokine receptor CXCR4) introduced earlier. The development and results obtained with these peptides are discussed below.89Zr to daratumumab by using the deferoxamine chelator  . Differechelator . Specifiatumumab . At late with MM . Becauseltration .90Y-DOTA complex  or a pretargeting RIT. In their first study, an Ab functionalised with streptavidin was combined with radiolabelled biotin . This pr complex . This biraftment .212Pb, 225Ac and ²¹³Bi  is another antigen expressed by most MM cells but absent in normal bone marrow cells. The group of Chérel et al. initially studied the therapeutic potential of er 177Lu , 134. Moer 177Lu . The biopatients . The tox68Ga-Pentixafor for CXCR4-directed PET were carried out in patients with lymphoproliferative diseases, i.e., NHL and MM. The further clinical development of these CXCR4 ligands was mostly studied in MM. In a first pilot study, 68Ga-Pentixafor PET correctly identified myeloma disease in 70% of the patients included in the study. These results were confirmed in a larger study by Lapa et al. in which 68Ga-Pentixafor uptake was shown in myeloma lesions of 23/34 MM patients  state) and was able to inhibit disease progression in treated mice as compared to the control groups , which can be quantified in serum samples and used for monitoring of the disease. The variable region of this immunoglobulin is the product of a unique recombination of gene sequences and is referred to as an idiotype . These il groups . In the ing mice .225Ac-labelled CS1 sdAbs, administered at a stage of low tumor burden (<5% tumor cells in bone marrow and spleen) significantly prolonged the survival of 5TMM mice  is another MM antigen for which different T-cell engaging therapies have been developed. BCMA, also called tumor necrosis factor receptor superfamily member 17, regulates B cell proliferation and survival, as well as maturation and differentiation into plasma cells . Similarnd ratio .89Zr was investigated as a potential PET agent for imaging of CD30 expression in murine models of lung cancer , is a protein expressed by activated B- and T-cells. This receptor is overexpressed in both B- and T-cell lymphoma. An Ab–drug conjugate (ADC) targeting CD30 (brentuximab vedotin) was developed by connecting an anti-CD30 mAb to an anti-mitotic agent monomethyl auristatin E . This cog cancer . Anothera tumors . The sama tumors . To stude tumors .131I-labelled anti-CD33 Ab in patients with relapsed AML  expressed on AML blasts  in untreated older (>60) patients with AML. Lintuzumab was also coupled to 213Bi and subsequently used in a phase I clinical trial including 18 patients with relapsed/refractory (R/R) AML  AML . Repeatee effect . This rae effect . More re studies .68Ga and 77Lu, respectively, and tested in patient-derived xenografts. 68Ga-Pentixafor enabled visualization of leukemic burden in the spleens and bones of NSG mice and correlated with CXCR4 surface expression  is the CXCR4 antigen. The previously mentioned peptides, Pentixafor and Pentixather, were labelled with pression . Interes concept .Most mAbs in development for the treatment of B-cell acute lymphomblastic leukemia (B-ALL) target the cell surface markers CD20, CD19 or CD22. The CD20 antigen can be found in about 30 to 50% of the B-cell precursor ALL, whereas CD19 and CD22 are present on the cell surface in over 90% of B-cell ALL . Blinatu90Y-epratuzumab on NHL were described in the dedicated section above. This radioconjugate was also tested in a phase 1 clinical trial that included 17 relapsed or refractory CD22+ B-ALL patients who received 4 increasing dose levels. One case of long-lasting aplasia was observed at the highest dose level, but besides the expected pancytopenia and mild infusion reactions, these administrations were well tolerated (111In or 125I-labeled anti-CD19 mAb was able to detect ALL cells in a severe combined immunodeficient (SCID) mouse model engrafted with primary human leukemia cells  selectively accumulate in human cancer cells as compared to normal cells and can be used for the selective delivery of diagnostic imaging and therapy agents to malignant tumors. These PLE accumulate due to an altered lipid metabolism in cancer cells. Well-designed derivates of alkylphosphocholine (APC) have been identified that show a prolonged sequestering in malignant cells. NM600 is such an APC analog that can be conjugated to a DOTA chelator and labelled with the positron-emitter 0Y-NM600 .90Y-NM600 induced strong anti-tumors effects and a T-cell mediated immune response, illustrated by the absence of tumor development after a second inoculation of lymphoma cells in mice that obtained a CR after TRNT. Similar APC analogs, such as CLR1404 (Cellectar Biosciences), are in development and currently tested in clinical trials, including B-cell malignancies and MM  and Astatine-211 (211At). 211At has a favorable radioactive decay scheme, and several different conjugation strategies can be proposed. However, it is produced in a high-energy cyclotron (28 MeV) by irradiation of a natural bismuth target, but its short half-life of 7.2 h makes the logistics challenging, as a limited number of medical cyclotrons are currently supplying the radionuclide. The success of 211At-based therapeutic radiopharmaceuticals will hopefully increase the availability of appropriate cyclotron production facilities.In addition to financial limitations, access to certain radionuclides is restrained. This is particularly true for alpha-emitters with a short half-life such as Actinium-225  and as an adjuvant treatment, complementary to standard treatment options. Unfavorable outcome with rapid disease progression following first-line treatment is still experienced in several hematological malignancies, such as aggressive B- or T-cell lymphoma and both acute lymphoblastic and myeloid leukemia. When the radiotheranostic agent has been proven clinically active, superior to the current standard of care approaches and accompanied by a manageable toxicity, this might encourage hematologists to offer this treatment to their patients.With the introduction of smaller antibody fragments, sdAbs and scaffold proteins, this toxicity profile will be changing. The major concern of mAb-based RIT will still be bone marrow toxicity in case of tumor infiltration. With the use of directly-labelled sdAbs or scaffold proteins, potential kidney toxicity could appear because of the high renal retention of these radioconjugates. Different pretargeting strategies are being explored to decrease this renal retention.To avoid toxicity, more specific tumor antigens could be targeted. Neoantigens are mainly tumor-specific antigens generated by mutations, alternative splicing or gene rearrangement in tumor cells, and generally absent on the surface of normal cells . The expWhile current TRNT approaches target the bulk of the tumor, future strategies should also focus on tumor stem cells. Further studies on antigen-expression in these stem cells are necessary to develop new treatment strategies. Another hurdle is the loss of antigen expression that may cause resistance to agents that bind to one single antigen. Promising approaches consist of targeting dual antigens, where one of the antigens is expressed in tumor progenitor cells.The potent and concentrated deposition of cytotoxic radiation in the case of α-particle emitters should be particularly interesting in the treatment of MRD settings, where isolated cells and small tumor clusters prevail. These residual cells ultimately cause relapse, often resulting in treatment-refractory disease. The elimination of MRD prior to stem cell transplant has been associated with improved OS in patients with hematologic malignancies, including ALL, AML and MM . Today, Theranostic radiopharmaceuticals offer an unique opportunity to perform high-resolution quantitative whole-body PET/CT imaging to provide clinicians with precise tumor phenotype and topography, enabling the identification of patients for TRNT. Early clinical trials illustrate the feasibility of mAb-based RIT, but their transition into clinical practice has slowed down. The recent development of radiolabelled PSMA-ligands and CXCR4-binders has triggered new interest in a rapidly expanding field with the introduction of Ab fragments, scaffold proteins, alpha-emitting radionuclides, and innovative conjugation techniques. The management of different hematological malignancies, such as multiple myeloma, lymphoma, and even acute leukemia will benefit from the progress and further facilitate the development of an optimal personalized theranostic agent, helpful for diagnosis, prognosis, and treatment.JC, ED, LV, and KV drafted the manuscript. ND and NW helped in conceiving this work. GM, VB, AK, ML, NW, ND, MD, AK, and MDH revised, read and approved the manuscript. All authors contributed to the article and approved the submitted version.ED, ML, LV, and VB are FNRS fellows. KV and MDH arepostdoctoral fellows of the Fonds Wetenschappelijk Onderzoek (FWO), MD is a research associate supported by the Fonds National de la Recherche Scientifique (F.N.R.S). The laboratory of Hematology was supported by Foundation Against Cancer,the CHU de Liège, the Fonds National de la RechercheScientifique  and the Fonds spéciaux de laRecherche (University of Liege). JC is a post-doctorate clinicalspecialist funded by the Belgian Foundation against Cancer.MD’H and ND are respectively employee and consultant of Precirix NV and hold ownership interest (including patents) in sdAb radiodiagnostics and radiotherapeutics. ND is a co-founder of Abscint and together with MD’H is a co-founder of Precirix NV.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Emerging evidence indicates that emotion processing deficits are associated with nonsuicidal self-injury (NSSI). However, limited attention has been paid to the socio-affective functions of NSSI. In this study, we aimed to investigate the affective theory of mind (ToM) in medication-free individuals engaging in NSSI at both behavioral and neural levels. Twenty-eight individuals (mean age = 22.96 years) who engaged in NSSI and 38 age-, sex-, and IQ-matched controls (mean age = 22.79 years) underwent functional magnetic resonance imaging while performing the “Reading the Mind in the Eyes Test” (RMET). All participants also completed the Difficulties in Emotion Regulation Scale (DERS), Toronto Alexithymia Scale (TAS-20), and Beck Scale for Suicide Ideation (BSI). Although we did not find significant group differences in the RMET performance, the NSSI group, relative to the controls, exhibited significantly greater left medial superior frontal lobe activation and decreased right angular gyrus activation than did the control group. Reduced right angular gyrus activity was related to higher DERS and TAS scores across all participants. Our findings provide new evidence for aberrant neural processing of affective ToM in self-injurers. Future studies in developing intervention protocols for NSSI should focus on the multifaceted phases of socio-affective processing. Nonsuicidal self-injury (NSSI) is defined as the deliberate damage to one’s body tissue without conscious suicidal intent . CurrentThe most recent Diagnostic and Statistical Manual of Mental Disorders  identifiMore specifically, there is evidence of a relationship between NSSI and emotional processing deficits such as facial emotion recognition difficulties , alexithU test total score = 57.5) in their pilot experimental study which aimed to verify potential difficulties in facial emotion discrimination in adolescents with NSSI diagnosis.Of note, interpersonal vulnerabilities have also been suggested as the core psychopathology for the development and maintenance of NSSI in Nock’s hypothetical model . HoweverThe RMET was originally designed to assess the theory of mind (ToM) deficits in high-functioning autism by Baron-Cohen et al. . ToM, a In the RMET, participants are asked to select one adjective out of four alternative labels that best describe the mental state depicted in an eye region photograph. The successful completion of the RMET requires the ability to infer and attribute others’ complex emotional mental states rather than simply label emotions . Given tPrevious functional neuroimaging studies have found that affective ToM recruits broad brain areas, including the bilateral medial prefrontal cortex, temporoparietal junction (TPJ), and middle temporal gyrus –40. A neIn summary, we aimed to identify neural mechanisms underlying affective ToM in NSSI. We hypothesized that individuals who cope with distress by engaging in repetitive self-injury might exhibit altered neural activity in response to the affective ToM task adopted from the RMET. Given the advantages of using neuroimaging research , we expeTwenty-eight medication-free participants (21 women) engaging in NSSI and 38 age-, sex-, and IQ-matched controls (26 women) without current illness were recruited through word-of-mouth and advertising on social media pages. The 28 participants enrolled in the NSSI group had engaged in five or more NSSI episodes in the past year. The Structured Clinical Interview for DSM-5 Disorders (SCID-5)  was admiThe exclusion criteria were as follows: (1) lifetime occurrence of psychotic symptoms or neurological disorder history; (2) current psychiatric treatment; (3) medication use in the previous month; (4) estimated IQ on the short form of the Korean version of the Wechsler Adult Intelligence Scale, Fourth Edition  < 80  = 210 mm, and flip angle = 90°]. T1-weighted multiband high-resolution images were also acquired for structural analysis with the following sequence: .All structural and functional images were acquired using a 3.0-T Siemens Trio MRI scanner  at the Seoul National University Brain Imaging Center. All images were acquired using a 32-channel head coil. A series of 37 slices parallel to the anterior-posterior commissure plane, with a thickness of 3.4 mm, were collected using a T2*-weighted spin echo-planar image  sequenceWritten informed consent was collected from the participants. Then, participants completed MRI scans and self-reported questionnaires. In this procedure, one participants’ questionnaire was missing.The RMET  was emplEach condition consisted of 28 trials in a pseudo-randomized order and started with example trials. A total of 56 trials, divided into two sessions, were preceded by one practice trial. Each trial was shown for 8 s, separated by a jittered intertrial interval  with a w1). Slice-timing correction was first executed, with the mean images being corrected to compensate for head motion. The EPI images were registered on T1-weighted images. Gray matter, white matter, and cerebrospinal fluid were segmented with each other, serving the forward deformation field. Normalization to an EPI template based on the Montreal Neurological Institute (MNI) reference brain was performed. The images were analyzed using a 6-mm full-width at half-maximum isotropic Gaussian kernel. None of the participants had head movements exceeding 3-mm translation and 3° rotation.We preprocessed the structural T1-weighted images and EPI functional images using Statistical Parametric Mapping version 12 software  analyses included six motion parameters  defined as square-wave regressors for each stimulus presentation block convolved with a gamma function to approximate the idealized hemodynamic response and one regressor for experiment condition, which are onset durations of the stimuli modeled in regressors of interest only satisfied with the answer.RMET minus control (RMET > control) contrast to obtain an activation map that indicated only emotional identification, based on the GLM using SPM 12. For the second-level analysis, we used a two-sample t-test to show the difference in neural activation maps between the groups. In this study, we used a threshold of uncorrected p < 0.001 with a cluster size of 20 voxels (k ≥ 20) (T = 3.45), which is stricter than Lieberman’s proposal  which was suggested with the aim of minimizing the risk of type I  errors  and Microsoft Office Excel software.In the first-level analysis, we compared ) errors –56. We a) errors , 58 to at-test and chi-squared test to analyze participants’ demographic features, self-reported questionnaires, and task results. Correlational analyses  were also performed to test whether neural activations during RMET performance were related to clinical symptom severity using Pearson’s correlation analysis.We also conducted a two-sample p > 0.05 for all). In terms of the clinical measures, individuals with NSSI scored significantly higher on TAS-20 for alexithymia, DERS for emotion dysregulation, and BSI for suicide ideation compared to the controls . There was also no group difference in handedness as assessed by the Edinburgh Handedness Inventory , RT, or accuracy both in the RMET and control conditions (nventory .MNIxyz) = , Z = 3.98, uncorrectedP < 0.001, k = 21, peak level T = 4.25, RMET minus control condition contrast = 0.72, S.E. = 0.17; interval = 0.56; beta = ] during the RMET task , Z = 4.04, uncorrectedP < 0.001, k = 29, peak level T = 4.33, control minus RMET condition contrast = 1.00, S.E. = 0.23; interval = 0.76; beta = ] compared to the controls  8] [medial superior frontal gyrus; MNI coordinates  scores and DERS  scores (p > 0.05).There was no correlation between the BOLD data during RMET performance and indicators of NSSI severity  and clinical measures within each group. However, across all participants, brain activation in the right angular gyrus, which appeared to be decreased in the NSSI group compared to the control group, was negatively correlated with the TAS-20  scores . There wAffective ToM is essential for inferring, responding to, or caring about how the other person feels , 60. ThiPeople with a history of NSSI showed superior accuracy in detecting unfavorable social signals . KlonskyConversely, it should be noted that affective ToM function is closely related to the ability of emotion recognition as well . Mier etWe found that the activation in the right angular gyrus was decreased in individuals with NSSI during the RMET condition. The angular gyrus, the dorsal part of the TPJ, is involved in perspective-taking and ToM . In partAs such, it might be that the attenuated angular gyrus during affective ToM condition signifies a diminished capacity for self–other distinction at the mental-level , leadingIn particular, we found that the decreased magnitude of the neural response in the right angular gyrus was correlated with increased TAS-20 and DERS scores for all participants. Alexithymia and emotional dysregulation are both closely linked to self-injurious behaviors , 17, 82.Several limitations should be considered when interpreting our findings. First, because our study’s cross-sectional design cannot establish causality, so the current findings should be interpreted with caution. In addition, given that emotion recognition and affective ToM are intertwined, and that extensive brain networks are involved in emotion regulation and social information processing , 85, regIdentifying the neurobiological correlates of NSSI is critical for building a pathological model of NSSI. To date, strong neuroimaging evidence has shown a relationship between NSSI and emotion dysregulation; however, the understanding of the neurophysiology related to the socio-affective processes of NSSI remains limited. This study provides the first neuroimaging evidence of a functional imbalance within the social brain network during affective ToM processing in patients with NSSI and its clinical implications regarding alexithymia and emotion dysregulation. In particular, the current neuroimaging studies have postulated that increased medial prefrontal cortex activation and reduced right angular gyrus are promising correlates for the socio-affective processes of NSSI. A better understanding of the pathophysiological mechanisms of NSSI may allow us to offer suggestions for the development of evidence-based treatments or interventions targeting NSSI behavior.The raw data supporting the conclusions of this article are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Korea University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.GN, HM, and J-WH contributed to the conception and design of the study. GN organized the database. HM performed the statistical analysis and wrote the first draft of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This cohort study examines the prevalence of contraindications to nirmatrelvir-ritonavir in patients hospitalized with COVID-19. Among these options, nirmatrelvir-ritonavir (Paxlovid)1 These medical contraindications may be prevalent in patients with COVID-19 who are at high risk for progression to severe disease, as suggested by a recent study.3However, there are circumstances in which nirmatrelvir-ritonavir should not be used, due to the effect of ritonavir. Ritonavir may elevate the concentrations of drugs highly dependent on hepatic cytochrome P-450 3A (CYP3A) metabolism, potentially resulting in serious reactions. Conversely, coadministration with potent CYP3A inducers can significantly reduce nirmatrelvir concentrations, potentially leading to the loss of virologic response. Furthermore, patients with severe kidney impairment and severe liver impairment were excluded from the clinical trials.We examined the prevalence of contraindications to nirmatrelvir-ritonavir in patients hospitalized with COVID-19. We hypothesized that the rate would be high in these patients.6 No patients received nirmatrelvir-ritonavir. We examined the proportion of patients with contraindications to nirmatrelvir-ritonavir in this sample and in those who died within 28 days of hospital admission, who thereby would have needed therapy other than nirmatrelvir-ritonavir in the ambulatory setting. We also stratified the analysis by sex, age (≤65 y vs >65 y), and comorbidity based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) main chapters. Medical contraindications of nirmatrelvir-ritonavir and criteria used to approximate them are detailed in STROBE reporting guidelines.In this cohort study, we applied individual medical contraindications listed by the US Food and Drug Administration for nirmatrelvir-ritonavir to a large sample of patients hospitalized with COVID-19, ascertained by a positive reverse transcription–polymerase chain reaction test, in 36 greater Paris University hospitals from January 24, 2020, to November 30, 2021.Of 63 656 inpatients with COVID-19, 1131 patients (1.8%) were excluded because of missing data for sex or age. Of the 62 525 remaining patients , 9136 (14.6%) had a medical contraindication to nirmatrelvir-ritonavir , with hi3 These findings also alert researchers to the risk of confounding by contraindication in observational studies focused on nirmatrelvir-ritonavir, which may overestimate treatment efficacy if not excluding patients with contraindications to this treatment. In addition, some of the contraindicated medications listed here could be temporarily held in the context of using nirmatrelvir-ritonavir.1In this study, contradictions to nirmatrelvir-ritonavir were prevalent in individuals hospitalized with COVID-19, as previously suggested.6Study limitations include that even if not contraindicated, treatment may not have been given to some patients due to symptom duration of longer than 5 days or limited supply, and information about vaccination, race and ethnicity, and weight was unavailable. These findings support the need to anticipate supplies for alternative approved treatments and those that are under regulatory review , and for continued research on less expensive treatment options for low- and middle-income countries.