The COVID-19 pandemic had a monumental impact on the inflammatory bowel disease (IBD) community. At the beginning of the pandemic, knowledge on the effect of SARS-CoV-2 on IBD was lacking, especially in those with medication-suppressed immune systems. Throughout the pandemic, scientific literature exponentially expanded, resulting in clinical guidance and vaccine recommendations for individuals with IBD. Crohn’s and Colitis Canada established the COVID-19 and IBD Taskforce to process and communicate rapidly transforming knowledge into guidance for individuals with IBD and their caregivers, healthcare providers, and policy makers. Recommendations at the onset of the pandemic were based on conjecture from experience of prior viruses, with a precautionary principle in mind. We now know that the risk of acquiring COVID-19 in those with IBD is the same as the general population. As with healthy populations, advanced age and comorbidities increase the risk for severe COVID-19. Individuals with IBD who are actively flaring and/or who require high doses of prednisone are susceptible to severe COVID-19 outcomes. Consequently, sustaining maintenance therapies  is recommended. A three-dose mRNA COVID-19 vaccine regimen in those with IBD produces a robust antibody response with a similar adverse event profile as the general population. Breakthrough infections following vaccine have been observed, particularly as the virus continues to evolve, which supports receiving a bivalent vaccine booster. Limited data exist on the impact of IBD and its therapies on long-term outcomes following COVID-19. Ongoing research is necessary to address new concerns manifesting in those with IBD throughout the evolving pandemic. In April 2021, Crohn’s and Colitis Canada’s COVID-19 and IBD Taskforce produced the 2021 Impact of COVID-19 & Inflammatory Bowel Disease in Canada. This report summarized the key learnings of the impact of COVID-19 on the IBD community at the one-year anniversary since the COVID-19 pandemic was declared by the World Health Organization. During the first year of the pandemic, and before the widespread dissemination of COVID-19 vaccines, the body of the scientific literature was synthesized and communicated to the IBD community through Crohn’s and Colitis Canada’s COVID-19 and IBD Taskforce using online resources and a webinar series. The scientific literature from that time period suggested that those with IBD shared a similar risk of becoming infected by SARS-CoV-2 or experiencing severe outcomes as the general population with the primary exception being those flaring and/or requiring high doses of oral systemic corticosteroids. During the first year, lockdowns and shielding populations believed to be at high risk, like the IBD community, reduced the risk of transmission. However, mental health distress was prevalent due to isolation and uncertainty of risks, which was exacerbated in immunocompromised individuals with IBD. Major breakthroughs in novel SARS-CoV-2 vaccines and antiviral therapeutics, as well as adaptation to models of healthcare delivery  offered hope that the second year of the pandemic would realize the easing of restrictions. Crohn’s and Colitis Canada’s COVID-19 and IBD Taskforce compiled knowledge and communicated with the IBD community through an expert-generated website and frequent webinars for a public audience. This work has set the stage for Crohn’s and Colitis Canada to inform the IBD community in the event of any future public health emergencies.Infection of SARS-CoV-2 for those with IBD is similar to the general population. Those with IBD are not at increased risk of acquiring COVID-19 or experiencing severe COVID-19 outcomes.Persons with IBD who require a high dose (>20 mg/day) of corticosteroids are at higher risk of experiencing severe complications from COVID-19.Those with IBD under the age of 50 who are actively flaring are at higher risk of severe COVID-19 outcomes.Maintenance therapies  for IBD are not associated with more serious disease course following infection from SARS-CoV-2.Vaccines for COVID-19 are safe and elicit robust immune responses to SARS-CoV-2 infection following three doses of vaccine in individuals with IBD, although immunity is less robust among those receiving prednisone to treat a flare or those on anti-TNF treatments.As breakthrough infections following vaccination occur at an increasing rate for subvariants of Omicron, a booster dose with a bivalent vaccine is recommended for those with IBD.Guidance to the IBD community consistently recommended to continue IBD therapies during the pandemic to avoid flaring from lack of adherence.Inflammatory bowel disease (IBD) affects more than 0.8% of the Canadian population in 2023 . When thExpert reviews of population-level recommendations were tailored to the IBD community and communicated through website FAQs and infographics ; a publiCrohn’s and Colitis Canada’s 2021 Impact of COVID-19 and IBD report synthesized the knowledge learned by the COVID-19 and IBD Taskforce . The purThe global pandemic was in part driven by the high transmission of SARS-CoV-2. Earlier in the pandemic, concern was raised that those with IBD might be at higher risk of being infected by SARS-CoV-2. The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is an international cohort study that recruited over 6000 individuals with IBD who were diagnosed with COVID-19 . AnalyziOverall, the accumulating data consistently demonstrated that the risk of severe COVID-19 in the general population was similar to those with Crohn’s disease or ulcerative colitis . MoreoveNumerous studies assessed the risk of severe COVID-19 in relation to the medications used to treat IBD. By July 2020, the first 500 cases reported in SECURE-IBD provided clues on the risk of drugs on severe COVID-19 . In contThe approval of the first mRNA and nonreplicating viral vector vaccines against SARS-CoV-2 occurred in December 2020 . ThroughA large prospective cohort study in Calgary, Alberta established the immunological efficacy of a three-dose mRNA vaccine series for those with IBD . FollowiPrior to the Omicron variant becoming the dominant strain, before December 2021, breakthrough infections following the completion of a vaccine series in those with IBD were not common. In a large cohort study in the United States, completed before December 2021, only 1.7% of individuals with IBD reported COVID-19 more than one month after completing their vaccine series . MoreoveStudies conducted during the Omicron wave (December 2021–present); however, have reported considerably higher breakthrough infection rates in those with IBD due to the highly infectious transmissibility and vaccine evasive subvariants of Omicron. The CLARITY-IBD study demonstrated that, during the Omicron wave, 15% of individuals with IBD experienced a breakthrough infection after a three-dose SARS-CoV-2 vaccine regimen . AlthougOverall, the short-term adverse events to SARS-CoV-2 vaccines in those with IBD are similar to the general population. A cohort study from the US showed that the most commonly reported adverse events after receiving a vaccine were: injection site pain, fatigue, and malaise; the rate of reporting in those with IBD was not different than healthy controls . AdverseOverall, the long-term complications of COVID-19 in those with IBD appear to be similar to the general population ; though,et al. this volume)  . Consequ volume) , which w volume) .Crohn’s and Colitis Canada’s COVID-19 and IBD Taskforce synthesized the medical literature during the pandemic in order to communicate timely and insightful guidance to the IBD community. Over the last three years, since the onset of the pandemic, the knowledge on the impact of COVID-19 on those with IBD has expanded dramatically. The risk of COVID-19 among those with IBD is similar to the general population. Individuals with IBD had similar risk factors for severe COVID-19 as the general population, namely age and comorbidities. Those with IBD who flared and were administered prednisone were at risk for severe COVID-19 outcomes. Vaccines served as the primary preventative health measure. Individuals with IBD require at least a three dose SARS-CoV-2 vaccine regimen. In addition, bivalent vaccines are recommended due to breakthrough infections and immune-escaping variants of the virus. Importantly, SARS-CoV-2 vaccines are safe in those with IBD and do not trigger a flare of disease activity. Data on the long-term impact of COVID-19 in people with IBD are lacking. Despite actions to guide the IBD community through the pandemic, those with IBD struggled with mental health concerns and impaired quality of life during the pandemic.There is still work to be done to understand the impact of public health recommendations geared to immunocompromised populations on the risk of infection by SARS-CoV-2.Determining the vaccine regimen that provides robust and durable serological response in those with IBD who are immunocompromised requires ongoing research.Exploring the effect of bivalent vaccines in reducing breakthrough infections following vaccination will be important for future studies.Determining the mental health sequelae and risk of long-term sequelae of COVID-19 (Long COVID Syndrome) in those with IBD is necessary.Lessons learned from the COVID-19 pandemic to prepare the IBD community for future viral outbreaks should be documented and incorporated into emergency planning measures.Patient partners emphasized that the risks of acquiring COVID-19 and the outcomes of COVID-19 are similar in individuals with IBD as they are for the general population. Preventing disease exacerbations and the need for high-dose steroid use are important to avoid more severe complications related to COVID-19. Partners stressed the importance of continuing with IBD-related medication therapies to prevent disease flare-ups and the need for steroid use. COVID-19 vaccines were recognized as safe for individuals with IBD. Encouragement should be provided to individuals with IBD to receive bivalent vaccine boosters to allow for continued protection against COVID-19. Information provided in this article provides peace of mind and reassurance to patient partners, allowing them to make educated decisions about their physical and mental wellbeing. Patient partners encouraged greater access to mental health supports for pandemic-related isolation, stress, and anxiety that many individuals experienced. Partners recognized there were some individuals, such as those in active flares and/or on >20 mg/day of prednisone, who remain clinically vulnerable or who may experience increased vulnerability to worse COVID-19 outcomes if they contract the virus. Ongoing protection and advocacy efforts need to center around these clinically vulnerable individuals. It was recommended that individuals perform their own risk assessment based on the scientific information available.Crohn’s and Colitis Canada’s COVID-19 and IBD Taskforce served as an invaluable resource to synthesize rapidly evolving information on the pandemic and communicate this knowledge to the IBD community via online sites and webinar series.Crohn’s and Colitis Canada can educate healthcare providers on the appropriate guidance of managing IBD throughout the pandemic, especially on the importance of receiving bivalent vaccines.Crohn’s and Colitis Canada should continue to advocate to policymakers and health authorities during the pandemic for vulnerable immunocompromised individuals with IBD.


As the fibula free flap became the gold standard in mandibular reconstruction that required both hard tissue and soft tissue, various methods have been sought to solve the height discrepancy between the mandible and fibula. The purpose of this paper was to propose a surgical option that combined the microvascular fibula free flap with a 3D-bioprinted, patient-specific polycaprolactone (PCL) implant as a safe and simple novel method that achieved the best functional and aesthetic results in mandibular reconstruction surgery for young patients with malignant tumors. The patient’s reconstructed mandible maintained volume symmetry without any deformation or complications for over 6 years. Computer-aided design/computer-aided manufacturing (CAD/CAM) and 3D printing technology enabled accurate and safe surgical results. Extensive mandibular defects resulting from malignant tumor resection require the reconstruction of mandibular continuity, taking into account both function and aesthetics ,2. In moThe purpose of this paper is to propose a novel surgical option that combines a microvascular fibula free flap with a patient-specific, 3D-bioprinted PCL implant to achieve a simple two-layer reconstruction while eliminating the technical difficulties in double-barreling. To the best of our knowledge, this is the first long term follow-up case to combine an osteocutaneous fibula free flap and 3D-bioprinted PCL implant in mandible reconstruction.A 24-year-old female patient was identified with osteosarcoma of the left mandible body and referred to Kyung Hee University Dental Hospital. Preoperative enhanced computed tomography (CT) and enhanced magnetic resonance imaging (MRI) confirmed a tumor of approximately 2.5 cm that had eroded the buccal cortical bone and was bulging out . A wide Our patient was a young female, and a more complete reconstruction result was desired without compromising both function and aesthetics, unlike in the case of an elderly patient suffering from a malignant lesion. Additionally, as the tumor was malignant, not benign, a simple and rapid reconstruction operation was necessary to minimize the risk and complications in consideration of the possibility of subsequent treatment. Therefore, considering all of the above, we devised a design that combined the fibular segment and the bio-printed PCL scaffold in two layers instead of the double-barrel method. The fibular portion was placed at the alveolus level for load-bearing and subsequent dental implant insertion, and the PCL scaffold was positioned beneath it to reproduce the patient’s original mandible border contour. This idea was made possible by computer-assisted design/computer-assisted manufacturing (CAD/CAM) and 3D printing technology.®, Materialize NV, Leuven, Belgium). The mass was extracted by overlapping the enhanced MRI data with the CT data  format. These datasets were imported into medical simulation software  to generate the skull and fibula models through segmentation processing. The standard tessellation language (STL) files of these 3D objects were transferred to medical CAD software , which produced it using medical-grade PCL  in Biofab’s 3D printing system. The PCL raw material was placed within a 10 mL steel syringe for printing. The PCL was heated to 120 °C, which was maintained for the printing duration. The molten PCL was then extruded through 500 µm steel nozzles. The printing code was generated by CAM software. The code was served to slice the customized 3D models and generated a moving path for the 3D printer to operate. The PCL scaffold was then fabricated with interconnected lattice-type pores E. This eThe surgical guides that we designed were directly printed using our own 3D printer  with clear resin , and these were sterilized by the hospital system.The left mandible and tumor were minimally exposed through simultaneous access to the neck and oral cavity without lip splitting. The transparent mandible cutting guides were adapted to the intended location, drilled in accordance with the fixing holes, and secured with screws A,B. The The osteofasciocutaneous fibula free flap with a fusiform skin paddle was obtained from the left lower leg by conventional lateral access. Before separating the vascular pedicle, the fibula cutting guide was precisely positioned on the outer surface of the fibula, drilled along the fixation holes, and monocortically fastened with screws. Then, piezoelectric osteotomy was elaborately implemented according to this fibula cutting guide, and the fibula free flap was harvested D. ImmediAfter placing the fibula segment on the defect of the mandible, the fibula positioning guide was accurately fixed with screws using holes already formed in the remaining mandible and fibula segment. In this state, the fibula segment and the remnant mandible were connected with mini-plates and mini-screws. The positioning guide was eliminated, and the patient-specific PCL implant was arranged below the fibula segment E. This sTo measure the density of the PCL implant using follow-up-enhanced CT and Mimics software, the same location where the PCL was positioned at the level of the maxillary first molar was identified in the coronal view. At this specific location, the mean value and standard deviation of the Hounsfield units (HUs) were obtained using the “density” function . To compThe patient was discharged without any complications after surgery, and the histopathological findings showed chondroblastic osteosarcoma, grade IV, with tumor-free margins. She underwent adjuvant chemotherapy with six cycles of high-dose methotrexate postoperatively and was followed up for over 6 years without metastasis, recurrence, or complications.The surgical results were analyzed using enhanced CT and MRI, which were radiographic images taken for the purpose of tracking malignant tumors. Follow-up CT scans were conducted at 2 weeks postoperatively and every year for the next 6 years, whereas MRI scans were performed only at 5 months, 11 months, 40 months, and 4-and-a-half years after surgery. The PCL implant exhibited similar attenuation to the surrounding soft tissue on the enhanced CT images, making it challenging to accurately generate a 3D model rendering in the Mimics software. The Hounsfield unit value of the PCL implant was measured using the “density” function in this software. It was observed that the density progressively increased over the years, from 75.50 at 2 weeks after surgery to 107.69 at 6 years after surgery . All aveAs shown in the series of facial clinical photos, the patient’s surgical site has been maintaining volume symmetry without any deformation for over 6 years, and the patient has been satisfied with her appearance C,D,F. DuThree years after cancer surgery, 2-stage dental implant  installation was performed outpatiently under local anesthesia, the final implant prosthesis was completed 4 years after surgery, and the patient recovered functionally and aesthetically .The purpose of this paper was to propose a surgical option that combined a microvascular fibula free flap with a patient-specific PCL implant as a safe and simple novel method that achieved the best results both functionally and aesthetically in mandible reconstruction surgery for young patients with malignant tumors.As the fibula free flap became the gold standard in mandibular reconstruction that required soft tissue and hard tissue simultaneously, various methods have been sought to solve the height discrepancy between the mandible and fibula, which was almost the only limitation ,9. TheseIn order to overcome the restriction of the double-barrel fibula graft and enable two-strut reconstruction , Lee et Polycaprolactone (PCL) is an FDA-approved, biocompatible, and biodegradable safety biomaterial that has been studied as a drug delivery device since the 1970s . RecentlHan et al. applied a patient-specific PCL scaffold to reconstruct a complex maxillary defect and reported stable and aesthetic surgical results . The HouThree-dimensional, metal-printed, patient-specific implants (PSIs) have been attempted as replacements for bone flaps in mandible reconstruction, and titanium (Ti) is preferred mainly due to its advantages such as its high tensile strength and osseointegration properties ,28,29. OCAD/CAM and 3D printing technology ensure the accuracy of reconstruction, reduce operation time and ischemia time, and, eventually, improve surgical results ,15,34. TThis new surgical option, which combines the free fibula flap with a 3D-bio-printed PCL, ensures optimal aesthetic results while guaranteeing function in mandibular reconstruction. A patient-specific PCL implant that shares the screw holes of surgical guides improves the accuracy, simplifies the operation, reduces the operation time, and, consequently, enables safe surgical outcomes. Through long-term follow-up, we have shown that this method produces ideal surgical results and remains stable. It is expected that these positive outcomes will lead to considering the primary application of the combined design in the mandibular reconstruction of young patients.


Artificial intelligence (AI)-powered, robot-assisted, and ultrasound (US)-guided interventional radiology has the potential to increase the efficacy and cost-efficiency of interventional procedures while improving postsurgical outcomes and reducing the burden for medical personnel.in vitro US data.To overcome the lack of available clinical data needed to train state-of-the-art AI models, we propose a novel approach for generating synthetic ultrasound data from real, clinical preoperative three-dimensional (3D) data of different imaging modalities. With the synthetic data, we trained a deep learning-based detection algorithm for the localization of needle tip and target anatomy in US images. We validated our models on real, in vitro data making the proposed approach a promising method to create AI-based models for applications of needle and target detection in minimally invasive US-guided procedures. Moreover, we show that by one-time calibration of the US and robot coordinate frames, our tracking algorithm can be used to accurately fine-position the robot in reach of the target based on 2D US images alone.The resulting models generalize well to unseen synthetic data and experimental The proposed data generation approach is sufficient to bridge the simulation-to-real gap and has the potential to overcome data paucity challenges in interventional radiology. The proposed AI-based detection algorithm shows very promising results in terms of accuracy and frame rate.This approach can facilitate the development of next-generation AI algorithms for patient anatomy detection and needle tracking in US and their application to robotics.• AI-based methods show promise for needle and target detection in US-guided interventions.• Publicly available, annotated datasets for training AI models are limited.• Synthetic, clinical-like US data can be generated from magnetic resonance or computed tomography data.in vitro US data.• Models trained with synthetic US data generalize well to real • Target detection with an AI model can be used for fine positioning of the robot. Interventional radiology has been credited with a variety of benefits such as reduced recovery times, reduced rates and severity of post-surgical complications, higher patient acceptance rates, and higher cost efficiency . RecentlOf particular importance for such systems is the capability to continuously track the surgical tool and relevant anatomy during the interventional procedure to handle organ movement and breathing. Due to its cost-efficiency, portability, and absence of radiation damage concerns, ultrasound (US) is an ideal imaging modality for autonomous interventions performed by a robot. Compared to x-ray imaging, the US poses significant challenges for needle and anatomy detection due to its numerous image artifacts.Several US image processing methods have been proposed to improve needle visibility . Some auRecently, approaches based on convolutional neural networks have shown promise for needle detection in static three-dimensional (3D) –16 and tin vitro data collected from a triple-modality abdominal phantom using the Micromate robot by iSYS Medizintechnik GmbH  . In order to mimic a real intervention, we first delineated the needle initial position and angle of insertion, then we generated a straight trajectory for the needle to follow. The final scatterer maps were obtained by combining the background Cb and the needle Cn scatterer maps.The gray-scale image The synthetic radiofrequency signals generated by SIMUS were demodulated to obtain in-phase/quadrature signals. Those signals were beam-formed using a delay-and-sum to obtain B-mode images with a dynamic range in dB. We used three values  to generate images that vary in dynamic range.We simulated the following two scenarios using the aforementioned ultrasound simulation pipeline.i.e., the left atrium, is well visible) from the volumetric MRI data. To create a dynamic scene, we iterated through the 8 slices while simulating the needle insertion, resulting in 48 scatterer templates for the simulated intervention. Needle insertion angles at 40−60° were simulated. In total, 2,880 synthetic images were generated. Annotations for the left atrium (target) on the synthetic US images were adopted from the MRI dataset and the needle tip was annotated based on its pre-defined trajectory.This scenario generated synthetic data using a public, annotated, clinical 3D MRI dataset  of the hIn addition to the clinical MRI data, we used the publicly available CT scan of the triple-modality phantom   to generin vitro 2D B-mode images using materials and settings specified in Fig. To validate the detection algorithm trained on synthetic US images, we collected In this experiment, the robot with a US scanner (Clarius C3) attached was manually positioned on the CIRS 057A phantom. Fine-positioning using the robot was performed until the target lesion was visible in the US images. Once in position, the needle (iTP KIR17/20:T) was inserted at an in-plane angle of 40° up to a depth of 60 mm. We performed three interventions for a total of 670 US images. The ground-truth lesions and needle tip positions were labeled by hand.in vitro scenario, but with the dedicated 3D-printed phantom filled with commercial gelatin to simulate tissue. The resulting dataset was used to test the DETR algorithm. The insertion of the needle (iTP KIR17/20:T) was performed at 40, 55, and 60°, respectively. We performed 9 interventions for a total of 1,800 US images. This scenario only contains the needle tip with ground-truth position labeled by hand.Here, we used the same experimental setup as in the previous To detect the needle and the target in all the aforementioned scenarios, we adapted the state-of-the-art detection transformer (DETR) neural network  for US i-4 was used for the fine-tuning. The learning rate and weight decay for the backbone (ResNet-50) were set to 10-5 and 10-4, respectively. Xavier initialization was adopted for the weights, and the dropout was set to 0.1. We used the same loss function as proposed in literature  for all detections and the total loss for different testing datasets. Table synth#1-both) achieved an mAP of 95%, showing a very good detection accuracy. We also trained two additional models, one only for needle detection (synth#1-needle) and one only for the left atrium (synth#1-heart), respectively. While the former performed very well, achieving an mAP of 98%, the mAP decreased to 80% for the latter. The (synth#1-needle) model was evaluated with both in vitro datasets for needle tip detection accuracy. The mAPs of both the in vitro scenarios  were lower (77% and 74%) compared to testing with synthetic data.Tables synth#2-both) achieved an mAP of 97%. The models trained only for needle (synth#2-needle) or lesions (synth#2-lesion) showed an mAP of 98% and 95%, respectively. The (synth#2-needle) model was tested on both in vitro datasets. The first in vitro scenario was the same as the synthetic scenario#2; hence, we evaluated both the needle tip and the lesions (in-vitro#1-both), achieving an mAP of 83%. Then, we individually tested the needle tip detection (in-vitro#1-needle) and lesions detection (in-vitro#1-lesion), achieving an mAP of 85% and 81%, respectively. Finally, we tested the in vitro dataset #2 (in-vitro#2-needle) with an mAP of 86%.Table in vitro acquisitions with a similar configuration as in synthetic scenario#2 as the same CIRS Phantom is used to perform the needle intervention. We can observe that the needle and the lesion are properly detected using the DETR previously trained with synthetic data. Finally, Fig. in vitro US images of the 3D printed phantom filled with gelatin.Figure in vitro scenario#2 US images for the computation of the homography matrix H (six interventions) and its evaluation (three interventions). For the validation experiment, three needle insertions performed at different initial points and angles were performed. The estimated needle tip positions were obtained by projecting the MoCap coordinates into the 2D US space through the homography matrix H. The root mean square error of the projection expressed in the MoCap frame was 2.8 mm for all three evaluation insertions.We used the H matrix obtained in the calibration step. This enables one to position the robot such that the target can be reached with the needle. Figure Figure e.g., tumor lesions), the proposed US simulation pipeline can be used to generate training data for a variety of interventions, and even for patient-specific training data, without the need of time-consuming and error-prone manual annotation.A main challenge for DL-based algorithms is the need for large amounts of annotated data to train models of sufficient accuracy and robustness. While publicly available, annotated datasets for diagnostic imaging have been steadily increasing , 31, 32,We have illustrated the validity of our approach by training DETR networks with synthetic data generated by our simulation pipeline using two different simulated clinical use cases and two different imaging modalities. We have observed that the needle detection performed very well in both the synthetic testing datasets . Also, the lesion detection performed very well (95% mAP), while the left atrium detection decreased (80% mAP) due to the fact that the latter is a very challenging task. Absent publicly available benchmark datasets, a direct comparison to state-of-the-art AI-based detection methods is difficult. Moreover, the approaches proposed in literature so far focused mostly on needle detection and not the more challenging needle and lesion/organ detection. The authors in  achievede.g., in the reduction of radiation exposure while enhancing precision [A crucial aspect in minimally invasive interventions is the initial positioning of the surgical tool with respect to the target. Different studies have reported promising CT image-guided navigation with C-arm systems combined with remote-operated positioning and guidance systems , 34, resrecision . Under irecision  even thoin vitro testing dataset is not as high as when evaluating with synthetic data , the achieved performance is very good illustrating the sim-to-real capability of our data simulation and training approach. While we have validated our approach with in vitro data and feel confident that the results will translate to clinical data, this will be confirmed by future experiments. We have only evaluated the needle detection algorithm for situations where the needle is in-plane with the US imaging plane. Nevertheless, since the proposed method detects the needle tip (not the entire needle shaft), partially out-of-plane needle localization is still possible. We have observed in our experiments that the needle we have used is prone to slight bending. While this does not affect the accuracy of needle tip localization, it can have an adverse effect on the accuracy of the proposed “robot in reach of target method”. Needle localization accuracy with our algorithm was sometimes negatively affected if there are bright speckles in its vicinity.Even though the accuracy on the We will further investigate these aspects in our future work to be able to draw conclusions for a wider array of different clinical situations. We have so far not investigated the impact of organ movement due to breathing or external pressure on our method. We will address this challenge in our future work by integrating the needle and target detection outcomes in a more complex state estimation structure relying also on the robotic platform.


According to recent estimates, approximately 1.4%-4.5% of U.S. children suffer from peanut allergy.4 but no therapies were approved by the U.S. Food and Drug Administration (FDA) at the time of the review by the Institute for Clinical and Economic Review (ICER). The goal of desensitization is to decrease the likelihood that patients will react to an accidental exposure to peanut protein. However, desensitization does not imply tolerance—the ability to eat any amount of food containing peanuts without risk of a serious reaction.The primary approach to managing food allergies is to avoid the food. Research has focused on desensitizing patients by exposing them to increasing amounts of the food,5This evidence review examines the effectiveness and value of 2 technologies to desensitize patients with peanut allergy that are expected to be approved by the FDA: AR101, a form of oral immunotherapy (OIT), and Viaskin Peanut, as well as noncommercialized OIT for peanut allergy.6 The peanut flour is mixed into pudding, applesauce, or other foods. The dose is gradually increased every 2 weeks to a goal dose of 300 mg daily. A health care professional must observe the patient during the initial dose and each subsequent increase in dose . Therapy must be continued indefinitely to maintain desensitization.AR101  is peanut flour produced using Good Manufacturing Practices.7 The first patch is placed under the supervision of a medical professional, but subsequent patches can be applied at home. The patch is worn 6 hours a day for 1 week, then 12 hours a day for another week, and then 24 hours a day from then on. Therapy must be continued indefinitely to maintain desensitization.Viaskin Peanut (DBV Technologies) is a patch applied daily to the upper back (rotating the location) that delivers 250 mcg of peanut antigen for desensitization treatment.https://icer-review.org/material/peanut-allergy-final-evidence-report-and-meeting-summary/.ICER conducted a review of AR101, Viaskin Peanut, and OIT. In this article, we summarize the systematic literature review and meta-analysis of the clinical effectiveness of the drugs, the cost-effectiveness analysis, and the policy discussion with key stakeholders regarding the overall value of these therapies held at a public meeting of the California Technology Assessment Forum (CTAF) on June 11, 2019. The detailed report is available on the ICER website at We compared the clinical effectiveness of AR101 and Viaskin Peanut to standard of care, which is strict avoidance of peanuts. We also reviewed other forms of OIT, which are offered by some allergists but have not received FDA approval. The primary clinical benefit was desensitization, which was defined differently in each of the trials. The primary harms were system allergic reactions, use of epinephrine, and adverse events leading to discontinuation of therapy.7 Several important differences should be highlighted. The PALISADE trial of AR101 included older patients (aged 12-17 years) who are less likely to respond to desensitization therapy. The PALISADE trial also enrolled participants with a lower-eliciting dose (≤ 100 mg vs. 300 mg), suggesting that their allergy was more severe. The primary outcome in both phase 3 trials was a double-blind placebo-controlled food challenge to evaluate the effectiveness of immunotherapy. However, despite consensus guidelines to assess desensitization,8 the 2 trials used different protocols and doses to define desensitization. The PALISADE trial defined desensitization as tolerating 600 mg or higher of peanut protein. The PEPITES trial defined desensitization as tolerating 100 mg for patients enrolled with reactions at < 100 mg and 300 mg enrolled with reactions at 300 mg. Thus, the PALISADE trial of AR101 enrolled participants who were sensitive to lower doses of peanut protein and had a primary outcome that was more difficult to achieve.There were no head-to-head randomized or observational trials comparing the therapies. P < 0.001).6 In the PEPITES trial, the primary outcome required that the lower bound of the 95% confidence interval (CI) for the difference between the 2 groups be greater than 15%. In the trial, the observed difference was 21.7% (95% CI = 12.4%-29.8%).7 Since the lower bound (12.4%) was less than 15%, the trial did not meet its primary outcome.The primary benefit documented in both trials was desensitization. In the PALISADE trial, a greater percentage of participants randomized to AR101 met the definition of desensitization compared with those randomized to placebo ; epinephrine use ; and serious adverse events . These findings were consistent during the buildup and maintenance phases through a maximum follow-up of 5.8 years, although median follow-up was only 1.0 years. Among the 3 studies that assessed quality of life, there were no significant differences between the OIT and placebo groups. The systematic review concluded that high certainty evidence demonstrates that OIT considerably increases allergic and anaphylactic reactions for at least the first year despite effective desensitization without evidence of long-term benefits.A systematic review and meta-analysis of 12 randomized trials of OIT reported that a higher proportion of patients achieved desensitization .Given the potential need for lifelong treatment and the relatively short duration of the trials of AR101 and Viaskin Peanut (1 year), there remains considerable uncertainty about the long-term outcomes for AR101 and Viaskin Peanut. There is hope that the rates of systemic allergic reactions, epinephrine use, and reactions to accidental exposure will decrease with continued therapy, but this has not been demonstrated. The need for long-term therapy also raises concerns about adherence to treatment, particularly during adolescence and young adulthood, which could increase the incidence of severe reactions.https://icer-review.org/material/peanut-allergy-final-evidence-report-and-meeting-summary/.We estimated the lifetime cost-effectiveness of the 2 peanut allergy immunotherapies from a U.S. health care sector perspective using a Markov model. The cost-effectiveness model included 2 separate comparisons: (1) AR101 oral immunotherapy plus avoidance compared with avoidance alone, and (2) Viaskin Peanut plus avoidance compared with avoidance alone. Survival, quality-adjusted survival, serious adverse events (anaphylaxis), and health care costs were summarized over a lifetime time horizon for each treatment option. Full details on ICER’s cost-effectiveness analysis and model are available on ICER’s website at 10The costs of immunotherapy with AR101 and Viaskin Peanut were unknown at the time of the public meeting. Based on analyst estimates, we assumed placeholder costs of $4,200 per year for AR101 and $6,500 per year for Viaskin Peanut.11 We assumed that participants in the peanut desensitized health state had an improvement in utility that was 60% of the difference between utilities for the untreated with peanut sensitivity and peanut-tolerant health states. This assumed that benefit is the source of all of the QALY gains in the model.Trial-reported quality of life outcomes have not yet been published. Health state utilities were derived from the only study in the food allergy literature that included a preference-weighted measure. The estimates of utility were derived using parent-reported (for children) and adolescent-reported EuroQol-5-Dimension responses.The economic model estimated that the incremental cost-effectiveness ratios for the 2 therapies ranged from $88,000  per quality-adjusted life-year (QALY) for AR101 to $216,000  per QALY for Viaskin Peanut . In one-Long-term clinical evidence on immunotherapy was not available, and the short-term data suggested greater harm than benefit. The effect of peanut allergy on preference-weighted health-related quality of life is also not well characterized. The economic model used preference-weighted utility estimates from a convenience sample of Swedish children with food allergies compared with children without food allergies, so the effect of immunotherapy on QALYs may be inaccurate. Improvement in health-related quality of life (utility) for the desensitized health state were crucial for estimating the overall benefit of the immunotherapies, but there are no data supporting improvements in utilities using the 2 novel therapies or OIT.The ICER report on immunotherapy for peanut allergy was the subject of a CTAF meeting on June 11, 2019. Following discussion, the CTAF panel members voted that the evidence was not adequate to demonstrate the superiority of AR101 to standard of care (4-12) and that there was not adequate evidence to demonstrate the superiority of Viaskin Peanut to standard of care (4-12). Furthermore, they voted that the evidence was not adequate to distinguish between AR101 and Viaskin Peanut (0-16). Because there was not adequate evidence to demonstrate clinical benefit, no votes were taken on value.The CTAF panel voted on “other potential benefits” and “contextual considerations” as part of a process to signal to policymakers whether there are important considerationswhen making judgments about long-term value for money not adequately captured in analyses of clinical and/or cost-effectiveness. The results of these votes are shown in https://icer-review.org/material/peanut-allergy-final-evidence-report-and-meeting-summary/. Several key policy recommendations are described below:The policy roundtable discussion explored how best to translate the evidence and broader perspectives discussed into clinical practice and into pricing and insurance coverage policies. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website: Manufacturers should pursue further evidence development to provide greater certainty about the long-term safety and effectiveness of desensitization therapies. Evidence should not rely on short-term surrogate outcome measures such as desensitization.Prescribing peanut desensitization therapies should be restricted to specialists , or for those patients with inadequate access to allergists, by primary care physicians only in consultation with a specialist.Payers may consider limiting coverage for initiation of desensitization treatment to patients between the ages of 4-17 years who represent the population studied to date.Payers should not stop coverage at age 18 for patients who have been on continuous desensitization therapy.Both therapies led to higher rates of desensitization to peanut protein in a double-blind food challenge after 1 year of therapy. However, there were higher rates of serious adverse events, systemic allergic reactions, and greater use of epinephrine in the active treatment arm for both therapies compared with placebo treatment. These outcomes should have decreased with effective therapy but did not during 1 year of treatment. In addition, no improvements in quality of life or reductions in anxiety were reported.


The results show that the human vaginal and rectal bacterial microbiota converged during the last gestational trimester and into the 2nd month after birth, with a significant decrease in Lactobacillus species in both sites, as alpha diversity progressively increased in the vagina and decreased in the rectum. The microbiota convergence of the maternal vaginal-anal sites perinatally might hold significance for the inter-generational transmission of the maternal microbiota.The human vaginal and fecal microbiota change during pregnancy. Because of the proximity of these perineal sites and the evolutionarily conserved maternal-to-neonatal transmission of the microbiota, we hypothesized that the microbiota of these two sites  converge during the last gestational trimester as part of the preparation for parturition. To test this hypothesis, we analyzed 16S  For the mother, it remains important for health during and after birth6. Women undergo important physiological changes during gestation that also affect their microbiomes8. Vaginal Lactobacillus increase relative abundances during pregnancy and this is observed across American9, European10, African11, and Asian12 populations. The fecal microbiota also changes with pregnancy, with reduced richness, and increased abundances of Actinobacteria  and Proteobacteria7. Third trimester fecal microbiota induce increased pro-inflammatory responses in germ-free mice compared with those from the first trimester7. The vaginal microbiota may have increased diversity post-partum, driven in part by increases in species of anaerobes , and a reduction in Lactobacillus species9.The maternal vaginal microbiome is a primordial source of microbes for the developing newborn14.Since in addition to the vagina, babies are exposed at birth to the mother’s perineum, which is a potential connection between the microbiomes of the intestine and the vagina, both of which undergo gestational changes. We hypothesized that the rectal and vaginal microbiotas converge during the last gestational trimester. This would be consistent with the conserved transformation of the maternal microbiota for transmission to the next generation. In this work, we determined the ante- and post-partum vaginal and rectal bacterial community structure in 21 mothers who delivered vaginally and in 20 mothers who delivered by Cesarean section (C-section), whose samples were obtained as part of an earlier studyrRNA gene sequences with an average of ~20,000 sequences per sample were obtained  and late (month 8) in the third gestational trimester, and at 2 months post-partum, in 41 mothers  than in the postpartum period  identified in this dataset were compared between vaginal and rectal microbiota. Lactobacillus features related to L. iners, L. crispatus, and L. acidophilus showed major components in shared microbial composition communities between the rectal and vaginal microbiotas. These temporal changes were more pronounced in vagina than in rectum, as evidenced by showing less error rates in supervised classification of vaginal samples by time-points, in relation to rectal samples  mechanisms that will expose the neonate to the widest diversity of intestinal microbes to be transferred from the mother2. These biological roles of vaginal/rectal microbial convergence should be examined in further research. Limitations of this study included a small number of samples and a lack of control for the use of antibiotics during labor. Further studies should follow the maternal microbiota beyond 2 months post-partum and when it normalizes to the non-pregnant typical state.Mammals evolved separate canals for reproduction, urination, and defecation but the rectal and vaginal orifices are typically proximal, while the urethra is noth 2 Fig.  as shown7. The post-labor vaginal microbiota differs from the baseline non-pregnant state, and the gestational changes have been shown to persist for up to 1 year after birth9.Prior studies have shown that there is a large increase in beta-diversity in the maternal fecal microbiota in the third trimester, as the fecal microbial populations become more host-specific20, further supporting our findings of vaginal/rectal microbiota convergence. Indeed, proof of concept of gut microbiota restoration in infants born by C-section have been shown using both vaginal21 and fecal22 maternal sources. In any case, elective C-sections also have the confounding effect of antibiotics for the procedure, and will impair the post-partum observations. Although different body sites of the baby during birth are exposed to the same maternal microbiome, baby site selection effect is observable at day 2 after birth, in the gut, skin and oral microbiota21, as the developmental succession continues after the infant’s birth14. Gestational changes in the microbiota might also be relevant to pregnancy outcomes9, since the fetus receives products of the metabolism of the maternal microbiota24, although the direction of causality is not well-understood.Studies of mother-to-infant strain transmission show that the early infant gut microbiome contains maternal fecal bacteriaLactobacillus species related to shared microbial composition communities between the rectal and vaginal microbiotas, and found that the major species were L. iners, L. acidophilus, and L. crispatus. L. iners has been associated with vaginosis25, and L. crispatus and L. acidophilus are associated with the high Lactobacillus dominance vaginal profile in healthy women26. If these changes optimize the exposure of infants to the beneficial maternal microbiota, they are of adaptive value. More research is needed to understand both the dynamics and functional significance of the maternal microbiota during the critical peripartum period of maternal recovery and child development and across wider racial demographics.Although the pre- and post-partum changes in the maternal microbial communities are clear, the significance of these for infant health remains unknown. We used DADA2-based methods to predict 13. Vaginal -introitus- swabs were collected by the obstetrician and/or through self-collection by the mothers using sterile cotton-tipped swabs, a method shown to be reliable to quantify BV-associated bacteria27 and to identify vaginal bacterial structures28. For this analysis, we used rectal (n = 73) or vaginal (n = 75) samples from pregnant mothers in the early (weeks 23-35) or late (weeks 36-delivery) third gestational trimester and 2 months after delivery . The samples analyzed in this study consist of a subset of samples collected with informed consent according to a New York University Institutional Review Board-approved study that took place in New York City from 2011 to 2014. Participation was voluntary and included written informed consent.In this study, we prospectively collected samples from the vaginal introitus and rectum of 41 women during pregnancy and at 2 months postpartum, as reportedrRNA gene sequencing dataset, bacterial taxonomic compositions, and analyses of alpha-diversity  and beta-diversity (Unweighted/Weighted UniFrac distance30) were performed using QIIME 2 version 2020.631 and its associated plugins. The q2-demux plugin was used for the demultiplexing and quality filtering of raw sequencing reads. Qualified reads were trimmed and denoised with DADA232. All amplicon sequence variants (ASVs) were aligned using MAFFT33 and used to generate a rooted phylogenetic tree with FastTree 234. The q2-feature-classifier plugin35 was used to trim the 99% SILVA 16S rRNA gene database36 to the 515F-806R (V4) region, train a naïve Bayes taxonomy classifier on these sequences, and use it to taxonomically classify each ASV. For comparisons of bacterial diversity, all communities were rarefied to 4347 reads (lowest number of reads) per sample, to include all samples the dataset. To determine significant differences in diversity, the Kruskal–Wallis test was used as a non-parametric test. Linear discriminant analysis (LDA) effect size (LEfSe) was used to detect statistically significant differences in the representation of bacterial taxa in comparisons (LDA score >3.0)37. Also, ALDEx2 tools38, which uses clr-transformed data generated from 128 Monte Carlo instances, used to confirm the LEfSe results. The Welch’s t-test was used followed by Benjamini–Hochberg false discovery rate (FDR) correction, and effect size was calculated. To evaluate community separation in beta diversity, PERMANOVA (with 999 random permutations)30 was used. Supervised classification of vaginal and rectal samples by time-points based on the ASVs table collapsed to genus level was performed using a q2-sample-classifier39 based on Random Forest classifier40 and nested stratified 5-fold cross-validation.The 16S Further information on research design is available in the Supplementary InformationReporting Summary


Introduction: Pituitary apoplexy (PA) is a rare phenomenon, characterized by a hemorrhagic or ischemic event of the pituitary gland, most often in association with a pituitary lesion. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the strain of virus responsible for the internationally recognized global pandemic COVID-19. Multiple clinical manifestations associated with this virus have been described, ranging from asymptomatic, mild flu symptoms to acute respiratory distress syndrome, end-organ failure leading to death. Cases of patients with concomitant COVID-19 infections and PA are being further recognized in the literature, but the causal association between the 2 entities remains speculative. Objectives: The objectives of this case series are 3-fold: to describe additional cases of patients with concomitant COVID-19 infection and PA (1), to review the current evidence regarding this potential complication associated with a COVID-19 infection (2), and to discuss physiopathological hypotheses, treatments, and prognoses of this newly recognized association (3). Method: We conducted an electronic chart review of patients treated for PA with concomitant COVID-19 infection from March 2020 to December 2021. A literature review was performed using MEDLINE, Web of Science, and Embase databases to identify other cases of COVID-19-associated PA. Results: From March 2020 to December 2021, 3 patients presented to our center with PA following a symptomatic COVID-19 infection. Two of these patients developed PA symptoms days following the viral infection, whereas the third patient developed PA after a 2-month period. The 2 first patients were managed surgically because of persistent visual symptoms. Results from our literature review yielded 12 other cases of COVID-19-associated PAs. Conclusions: The association between COVID-19 infection and PA has been increasingly reported in the literature. With the addition of the 3 cases described in our article, a total of 15 cases have been published. Many contributing mechanisms may lead to PA following COVID-19 infection. Coagulopathy is probable major contributing cause responsible for hemorrhage or infarction of the pituitary gland. Our case series provides further arguments that PA may be a direct manifestation of a COVID-19 infection. Its incidence is difficult to evaluate and varies between 1% and 26% across the literature. The pathophysiology of PA is largely misunderstood and multiple hypotheses have been proposed thus far. Vascular compromise by outgrowth and compression by a macroadenoma are the accepted premises but fail to explain all cases of PA. However, the theory of expansion illustrates the clinical manifestations of the disease. The most frequently encountered symptoms being severe acute retro-orbital headache, nausea, visual impairment, and hypopituitarism. Diagnosis is based on computed tomography (CT) scan or magnetic resonance imaging (MRI) findings. Management of PA is either conservative or surgical. Evidence of severe disease with neurological deficits, visual field defects, and altered mental state generally require surgical management, but there is no consensus on criteria that warrant surgical versus conservative management.Pituitary apoplexy (PA) is a rare phenomenon, characterized by a hemorrhagic or an ischemic event of the pituitary gland, most often caused by a macroadenoma. There are multiple clinical manifestations associated with this virus, ranging from asymptomatic, mild flu symptoms to acute respiratory distress syndrome, end-organ failure and death. Vascular complications associated with the SARS-CoV-2, such as PA, are being further recognized in the literature.Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the strain of virus responsible for the internationally recognized global pandemic COVID-19. As of December 2021, the cap of over 260 million cases had been breached and over 5 million people have succumbed to the disease worldwide.We describe a case series of 3 patients presenting with PA and a concomitant infection to SARS-CoV-2 virus strain.A 65-year-old healthy man, presented to the emergency room (ER) with a persistent headache and left eye ptosis accompanied with a cough. Initial laboratory results revealed hyponatremia as well as a positive COVID-19 polymerase chain reaction test. A CT scan demonstrated an image compatible with a recent hemorrhage within a pituitary macroadenoma, causing PA. Further endocrine work-up revealed hypothyroidism, central adrenal insufficiency, as well as syndrome of inappropriate antidiuretic hormone, hyponatremia, all compatible with panhypopituitarism. On the third day of hospitalization, he developed ophthalmoplegia secondary to cranial nerve III, IV, VI paresis and ipsilateral hemianopia. An MRI, which was delayed due to patient claustrophobia, confirmed the presence of a macroadenoma with signs of recent hemorrhage, causing compression of the optic chiasma . ConsideA 61-year-old woman with a known, asymptomatic, pituitary macroadenoma, and an intellectual disability presented to our ER with fever and lethargy 6 days after testing positive for a COVID-19 infection. She was hospitalized and developed right oculomotor nerve paresis as well as central hypothyroidism and adrenal insufficiency. Both CT scan and MRI demonstrated an increase in size of her known macroadenoma with hemorrhagic contents . PA was An 89-year-old man previously known for hypertension and dyslipidemia developed a severe headache for which he presented to our ER. The patient had contracted and survived a COVID-19 infection 2 months prior to these symptoms. As initial laboratory work-up and CT scan imaging were negative, the patient was discharged with pain medication for a headache of unknown etiology. He sought medical attention 3 days later for a persistent, intense headache. A repeat CT scan demonstrated a 10-mm-thick lesion of the suprasellar region with heterogeneous enhancement associated with a suspected pituitary macroadenoma. He was admitted to the hospital and evaluated by the endocrinology team, who diagnosed him with panhypopituitarism. Initial MRI demonstrated an increase in size of the pituitary gland and enhancement compatible with internal hemorrhage of the lesion , diagnosThe 3 cases described herein are part of a scarce number of new reports of patients suffering from PA and a concomitant SARS-CoV-2 infection. To our knowledge, 9 case reports and 1 case series of 3 patients, for a total of 12 patients, have previously been reported in the literature. Results from our review of the literature are summarized in  in a case series describing 5 patients suffering from sudden hemorrhage of the pituitary gland. This clinical entity is defined as a rapid expansion of a normal or neoplastic pituitary gland by sudden hemorrhage or infarction. Its incidence is difficult to establish and varies in the literature between 1% and 26%. Most cases of PA present in the fifth or sixth decade of life, as is reflected in 2 of our described patients. Two of our 3 patients were of male gender, mirroring the male predominance suggested in the literature.PA was first described in 1950,14 Hypertension is in fact the most recognized precipitating factors of PA. It was also a frequently encountered comorbidity in previously published cases of patients with PA associated with COVID-19.15 PA is most often described with pituitary adenomas, but also can occur in glands suffering from hypophysitis, craniopharyngioma, Rathke cleft cysts, sellar tuberculoma, and sellar metastasis. In the cases described in this article, 1 patient had a known asymptomatic macroadenoma, whereas 2 patients presented were diagnosed initially with PA. In our review of the literature, 2 patients had the presence of a known macroadenoma while the others presented with PA as the first presenting sign.61315 Only 1 case presented with PA in the absence of an underlying pituitary tumor.Known risk factors of PA are hypertension, major surgery, dynamic testing of the pituitary gland, anticoagulation, dopamine receptor agonists, estrogen replacement therapy, radiation, pregnancy, and head trauma.), whereas 4 patients had up to 2 months of delay between COVID-19 diagnostic and neurological symptom presentation. In the cases described in this article, 1 patient presented with both symptoms and COVID-19, 1 patient developed PA a week following a positive COVID-19 test, and 1 patient developed PA 2-months following COVID-19 diagnosis.Adding our cases with the others that were already described, there are now 15 cases of patients who presented with PA after contracting a COVID-19 infection. This rising number of cases make it reasonable to believe that there may be a causal relationship between COVID-19 infection and PA. The temporality of this association is another argument for causality here. We found that 11 of the 15 patients described in the literature developed PA within 10 days of onset of COVID-19-related symptoms  and endocrine system. Entry into the CNS by coronavirus has been described through hematogenous or retrograde neuronal route, demonstrating the neurotropic and neuroinvasive capabilities of this pathogen. These statements corroborate with the finding of SARS-CoV viral particles in patients’ cerebrospinal fluid. The role of angiotensin-converting enzyme-2 (ACE-2) receptors has also been explored as an explanation for multi-organ involvement of the viral infection. ACE-2 receptors are found in the heart, gastrointestinal system, the CNS as well as in the coagulation cascade constituents and could act as points of entry of the virus inside the cells. Li et al demonstrated that ACE-2 can be immunoprecipitated by the S1 domain of SARS CoV-2 protein and that it can promote viral replication, proving its role as a functional receptor for the pathogen. This virus strain is therefore capable of neuroinvasion by direct viral infection of the gland, mediated by ACE-2 receptors.The pathophysiology of PA remains unclear but multiple hypotheses have been explored. The high energy demand and limited blood supply of underlying adenomas make it an anatomic location with a fragile equilibrium. Any alteration in the balance between tumor perfusion and tumor metabolism increases the risk or hemorrhage or infarction. are all plausible ways coronavirus infection could interrupt neural function and lead to PA. There has been evidence to show that the virus in question induces an intracranial cytokine storm syndrome and subsequent breakdown of the blood–brain barrier rather than direct neural invasion.Other mechanisms of interaction between the endocrine, neural systems, and SARS CoV-2 have been proposed. Activation of the hypothalamo-pituitary axis via inflammatory mediators as well as an immune-mediated glandular damage causing hypophysitis, secondary to antibody formation or cell-mediated damage described the cases of 4 young patients presenting with catastrophic, large arterial thrombosis at a median of 78 days from seroconversion from a COVID-19 infection. Two patients manifested large vessel ischemic stroke, one presented with an acute ischemic limb due to arterial thrombosis, and another had myocardial infarction. An increase in factor VIII, D-dimer levels, von Willebrand factor antigen, and hyperfibrinogenemia in these patients were suggestive of a hypercoagulable state. The duration of inflammation as well as thrombotic derangements induced by this novel viral infection has yet to be determined. A proposed state of endothelial activation and dysfunction and low-grade inflammation in the convalescent phase of the illness could be responsible for delayed thrombotic presentation and could explain both acute and late cases of patients suffering of PA following a COVID-19 infection. A systematic review by Tomerak et al also concluded that a hypercoagulable state is a common feature in many of the coronaviruses. A dysregulated immune response was found in these patients, leading to cytokine storm, endothelial cell activation, capillary leakage, hypotension, and hypercoagulation. Thrombosis ensues via activation of the coagulation cascade combined with downregulation of anticoagulating factors.Coagulopathy is another major probable contributing factor in the pathophysiology of PA following COVID-19 infections. As increasing cases were diagnosed worldwide, it rapidly became clear that COVID-19 infections had the potential to disrupt the coagulative hemostasis of patients and cause major thrombophilic complications. Fan et al15 In contrast, conservative management is recommended for patients with isolated oculomotor involvement, unimpaired level of consciousness, no visual impairment, and subclinical PA.15 More recent evidence has shown that conservative management leads to favorable visual and neurological outcomes. Beyond the risks inherent to the surgery, there may be additional surgical risks associated with COVID-19 infections, for both surgeons and patients. Zou et al analyzed viral loads of SARS-CoV-2 and determined that viral quantity was independent of symptom severity and that higher viral loads were detected in the nasal mucosa soon after symptom onset. Both intranasal and endoscopic skull base surgeries are therefore high-risk procedures in an infected patient, putting the surgical team at threat for viral infection. The surgical risks are not only limited to the operating room (OR) staff. Carrier et al demonstrated that COVID-19 patients undergoing surgery are at greater risk of pulmonary and thromboembolic complications as well as a 15.9% risk of mortality.Management of PA is also of great debate and both conservative and surgical treatments have been used in the management of PA. Of the 15 published cases, 8 patients were treated surgically. Decreased visual acuity or ocular nerve palsy was considered surgical indication in all cases. Five of these patients were urgently operated, with little or no delay between diagnostic and surgical decompression. In the cases presented in our series, 2 patients underwent non-urgent transsphenoidal surgery due to persistent ocular symptoms. Current evidence suggests that transsphenoidal optic chiasma decompression is the recommended surgery for patients with PA presenting with impaired consciousness, hypothalamic involvement, sudden onset amaurosis, and decreased visual acuity. This contrasts with other published cases in which the majority of patients underwent urgent surgical management of PA. Only 1 case was treated with delayed surgery: a 28-year-old pregnant woman presenting with PA and a COVID-19 infection, operated 7 days after PA diagnostic, the reason for the delay being to allow childbirth. This patient also experienced complete visual recovery. However, postoperative evolution is difficult to compare in this instance. Of the 15 patients described, 2 succumbed to the viral infection and 3 are lacking information concerning follow-up. It is worth mentioning that all patients treated with delayed surgical management had a favorable evolution. The role operative delay will play in future similar cases is yet to be determined.In the cases presented herein, delay in surgery was not associated with worse outcome. Both patients who were treated surgically had a complete recovery at the postoperative follow-up visit. The decision to delay surgery was mainly due to the risk of viral shedding from active infection as well as the lack of evidence concerning indications for surgery. These guidelines may be subject to change with the ongoing evolution of the COVID-19 pandemic.Finally, the SARS-CoV-2 pandemic has brought its fair share of obstacles related to surgical safety of staff members, access to the OR, and delays in surgery. These issues have forced us to revisit the operative indications for many surgical pathologies. The Pituitary Society Guidance recommends surgical delay in patients with COVID-19, ideally until they no longer have symptoms and have a negative swab test result. If emergent surgery is necessary and cannot be differed, they suggest alternative transcranial approaches to avoid nasal mucosa disruption. The replacement of high-speed drilling to non-powered tools as well as the use of large suction tubes to aspire particulate matter is recommended, jointly with the use of personal protective equipment.In conclusion, an association between COVID-19 infection and PA has been increasingly reported in the literature. With the addition of the 3 cases presented in our article, a total of 15 cases have been described. The possible relation between COVID-19 and PA is becoming more and more evident, but a causal relationship between the 2 entities remains largely speculative. Although PA is a rare condition, COVID-19 cases keep rising as new mutant viral strains develop. If this infection is in fact a risk factor for developing PA, it is important to understand the pathophysiological interaction of the 2 entities to recognize the clinical presentation, quickly introduce the appropriate treatment, and establish recommendations concerning management. Many contributing mechanisms may lead to PA following COVID-19 infection. Our case series explores numerous hypotheses which may explain how PA may be associated with COVID-19 infection through the multiple pathogenic mechanisms previously described. We believe that publication and sharing of these cases is paramount and will certainly contribute to care and treatment optimization in patients with COVID-19 and PA.


Our data suggest a transient decrease in the incidence of maternal primary CMV infection in Japan during the COVID-19 pandemic, which could be due to prevention and hygiene measures taken at the population level.This study evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on the occurrence of maternal primary cytomegalovirus (CMV) infection in Japan. We performed a nested case-control study using data from maternal CMV antibody screening under the Cytomegalovirus in Mother and infant-engaged Virus serology (CMieV) program in Mie, Japan. Pregnant women with negative IgG antibodies at ≤20 weeks of gestation who were retested at ≥28 weeks were enrolled. The study period was divided into 2015–2019 as the pre-pandemic and 2020–2022 as the pandemic period, and the study site included 26 institutions conducting the CMieV program. The incidence rate of maternal IgG seroconversion was compared between the pre-pandemic (7008 women enrolled) and pandemic  periods. Sixty-one women in the pre-pandemic period and five, four, and five women during 2020, 2021, and 2022, respectively, showed IgG seroconversion. The incidence rates in 2020 and 2021 were lower ( Cytomegalovirus (CMV) is a pathogen associated with mother-to-child transmission and is known to cause damage to the fetal central nervous system. Besides neurological dysfunctions, hepatological or hematological dysfunctions are well-known damage in infants. CMV infections are established through human body fluids, such as urine and saliva, from others. Maternal primary CMV infection during pregnancy often occurs through young children’s urine or saliva .Both maternal CMV infection before conception (non-primary CMV infection) and after conception (primary CMV infection) can cause congenital CMV (cCMV) transmission. Serological screening, including assessment of CMV immunoglobulin (Ig) G and IgM antibody levels and IgG antibody avidity, is used to identify mothers with primary CMV infection, which is associated with a higher risk of cCMV transmission than that of non-primary CMV infection. Maternal primary CMV infection is confirmed with CMV IgG antibody seroconversion during pregnancy and is suspected by a set of positive CMV IgG antibodies, positive IgM antibodies, and low IgG antibody avidity .Maternal CMV antibody screening is performed in Mie, Japan under a program called the Cytomegalovirus in Mother and infant-engaged Virus serology (CMieV) program ,3,4,5. TIn Wuhan, China, coronavirus disease 2019 (COVID-19) emerged at the end of 2019. COVID-19 spread rapidly across China and became a worldwide pandemic ,7. In JaAfter the onset of the COVID-19 pandemic, the epidemiology of some viral infections, such as influenza virus and respiratory syncytial virus, has changed in several countries. Under the situation, decreases in the incidence of infant cCMV infections have been reported in Portugal in 2020, Spain in 2020–2021, and the USA in 2020–2021 ,12,13. TTo our knowledge, to date, there is no study that reported a decrease in maternal primary CMV infection during the COVID-19 pandemic. Our aim was to evaluate the impact of the COVID-19 pandemic on the occurrence of maternal primary CMV infection during pregnancy in Japan using the CMieV cohort that was continued across the COVID-19 pre-pandemic and pandemic periods.This was a nested case-control study using data from the CMieV program. The program has contained a maternal CMV antibody screening and a newborn urine CMV DNA test and has been a population-based, mother–child, observational, prospective cohort study.As per the CMieV program, pregnant women are tested for serum CMV IgG plus IgM antibodies at ≤20 weeks of gestation. Pregnant women with negative CMV IgG antibody results are educated on how to prevent CMV transmission from other persons and instructed to avoid direct contact with infectious body fluids, such as urine and saliva of children and semen of male partners, during pregnancy. CMV IgG antibody testing is repeated at ≥28 weeks of gestation. Pregnant women with CMV IgG antibody seroconversion (negative results at ≤20 weeks and positive results at ≥28 weeks of gestation) are considered as having primary CMV infection during pregnancy. Their neonates are tested for the presence of CMV DNA in fresh urine specimens obtained within one week after birth. Neonates with positive fresh urine CMV DNA results are diagnosed with cCMV infection. Using the CMV DNA-positive fresh urine, viral isolation tests are performed .In the current study, pregnant women who were CMV IgG negative at ≤20 weeks of pregnancy and were retested for CMV IgG antibodies at ≥28 weeks were retrospectively enrolled in the CMieV program. The study period was from January 2015 to June 2022 (January 2015–December 2019 as the COVID-19 pre-pandemic period and January 2020–June 2022 as the COVID-19 pandemic period). The study site included 26 CMieV program institutions in Mie, Japan .CMV IgG antibody test was performed using enzyme-linked immunosorbent assay (ELISA) kits . In the current study, negative and positive IgG antibody results were defined by IgG titers of ≤3.9 and ≥4.0 ELISA values, respectively.Real-time polymerase chain reaction (PCR) was performed for CMV DNA detection in neonatal fresh urine samples as previously described . Gene nap value of ≤0.05 was considered statistically significant.The incidence rate of maternal CMV IgG antibody seroconversion was compared between the COVID-19 pre-pandemic (2015–2019) and pandemic  periods. The whole of the years 2020 and 2021 (January–December) were included, whereas in 2022 only the first 6 months (January–June) were included. Both annual (January–December) and semi-annual (January–June and July–December) incidence rates were studied. Similarly, the incidence of positive fresh urine CMV DNA results in neonates was compared between the COVID-19 pre-pandemic and pandemic periods. The annual (January–December) incidence rates were also determined. The incidence rate of maternal CMV IgG antibody seroconversion in each age group  and each parity group  was compared between the COVID-19 pre-pandemic and pandemic periods. Fisher’s exact test was used for comparisons using SPSS software , and a The numbers and clinical characteristics  of pregnant women enrolled during the COVID-19 pre-pandemic (2015–2019) and pandemic  periods are shown in p = 0.0451) and 2021 (p = 0.0486) were significantly lower, and that in 2022 (p = 0.2805) was not significantly different from that in the pre-pandemic period  and semi-annual (January–June and July–December) incidence rates of maternal CMV IgG antibody seroconversion during 2015–2022 are shown in p = 0.0480) and in the group of para 0 (p = 0.0492) for age and parity, respectively. Monthly incidences of maternal CMV IgG antibody seroconversion during the COVID-19 pandemic period are shown in The incidence rates of maternal CMV IgG antibody seroconversion during pregnancy in each age group  and each parity group  during the COVID-19 pre-pandemic and the COVID-19 pandemic periods are shown in In the present study, the incidence rate of maternal CMV IgG antibody seroconversion in 2020–2021 was significantly lower, and that in 2022 was not significantly different from that in the COVID-19 pre-pandemic period. This indicates that the incidence of maternal primary CMV infection transiently decreased during the COVID-19 pandemic in Mie, Japan; however, this decrease was reversed in 2022 to the same level as the COVID-19 pre-pandemic period. Further, the semi-annual incidence rates in the second half of 2020 and the first half of 2021 were low, whereas those in the second half of 2021 and the first half of 2022 were as high as in the COVID-19 pre-pandemic period.In the present study, significant differences in the incidence rate of maternal CMV IgG antibody seroconversion were found only in the group of thirties and over and in the group of para 0 for age and parity, respectively. We did not interpret the present results as indicating that only the thirties and over group decreased in age groups and only the para 0 group decreased in parity groups. We speculated that the small sample sizes of the teens and twenties groups and the para 1 and para 2 groups might have prevented us from observing a significant decrease in the incidence rate of maternal CMV IgG antibody seroconversion. First, the thirties and over group had a higher proportion of pluripara than the other age groups, making it difficult to link the thirties and over and para 0. Second, the thirties and over group actually had the largest sample size by age group, and the para 0 group also has the largest sample size by parity group. Thus, we assumed that the incidence rates of maternal CMV IgG antibody seroconversion in all age groups and all parity groups decreased during the COVID-19 pandemic period compared to that in the pre-pandemic period.p < 0.001) higher in teens (5.0%) than in older pregnant women  [We reported in the previous literature that the incidence rate of maternal CMV IgG antibody seroconversion was significantly  . As the r, 0.6%) . AlthougIn the CMieV cohort, the number of mothers with primary CMV infection significantly decreased during 2020–2021 compared to that in the COVID-19 pre-pandemic period. These findings can be explained as follows: First, extensive changes in personal and social behavior and the hygiene habits in daily life at the population level have reduced the transmission of SARS-CoV-2 and resulted in the end of the COVID-19 pandemic. One of the major routes of CMV transmission is direct contact with other’s body fluids, including urine and saliva. In Japan, the first, second, and third waves of COVID-19 came in 2020. The fourth and fifth wave came in 2021, and the sixth wave came in 2022. On 7 April 2020, a state of emergency was declared by Japan’s government . In response to the first state, a prefectural state of emergency was declared in Mie, Japan on 10 April 2020. COVID-19 vaccination began in April 2021. Under the state of emergency, residents were strongly urged to refrain from leaving their houses and moving unnecessarily, except when necessary to maintain their daily lives. Residents were strongly requested to take thorough actions to avoid enclosed, dense, and closed areas in cases when leaving the house was unavoidable. Since the major route of familial transmission of CMV to mothers is from young boys and girls attending daycare centers, this could be one of the factors contributing to the decline in maternal CMV infection during the pandemic ,16. ReceUniversal mask use and increased frequency of hand washing in daily lives during the pandemic might have also contributed to the decreased maternal primary CMV infection during the pandemic compared to that of the COVID-19 pre-pandemic period, as demonstrated in studies on other viral infections, such as influenza virus and respiratory syncytial virus ,21. VillIn the current study, we demonstrated a transient decrease in the incidence rate of maternal primary CMV infection during pregnancy in Mie, Japan during the COVID-19 pandemic period (2020 and 2021) compared to the COVID-19 pre-pandemic period (2015–2019); however, we could not statistically show a decrease in the incidence rate of neonatal cCMV infection in the same population as maternal primary CMV infection. This might be due to a statistically small number of neonatal cCMV infection observations compared to the three previous studies performed not in Japan ,12,13. AIn conclusion, the findings of the current study suggest a significant and transient decrease in the incidence of maternal primary CMV infection during the COVID-19 pandemic period in Japan compared to the COVID-19 pre-pandemic period. This was probably due to the prevention of SARS-CoV-2 transmission through personal and social hygiene measures taken at the population level to end the COVID-19 pandemic.


Genomic surveillance has emerged as a crucial tool in monitoring and understanding the dynamics of viral variants during the COVID-19 pandemic. In the Midwest region of Brazil, Mato Grosso do Sul has faced a significant burden from the SARS-CoV-2 epidemic, with a total of 613,000 confirmed cases as of June 2023. In collaboration with the Central Public Health Laboratory in the capital city of Campo Grande, we conducted a portable whole-genome sequencing and phylodynamic analysis to investigate the circulation of the Omicron variant in the region. The study aimed to uncover the genomic landscape and provide valuable insights into the prevalence and transmission patterns of this highly transmissible variant. Our findings revealed an increase in the number of cases within the region during 2022, followed by a gradual decline as a result of the successful impact of the vaccination program together with the capacity of this unpredictable and very transmissible variant to quickly affect the proportion of susceptible population. Genomic data indicated multiple introduction events, suggesting that human mobility played a differential role in the variant’s dispersion dynamics throughout the state. These findings emphasize the significance of implementing public health interventions to mitigate further spread and highlight the powerful role of genomic monitoring in promptly tracking and uncovering the circulation of viral strains. Together those results underscore the importance of proactive surveillance, rapid genomic sequencing, and data sharing to facilitate timely public health responses. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious coronavirus that emerged in late 2019, causing a global pandemic of acute respiratory illness known as ‘coronavirus disease 2019’ (COVID-19) and posing a significant threat to human health. The disease was first reported in Wuhan, Hubei province, China, with the World Health Organization declaring it a global public health emergency on 30 January 2020 . DiffereConvenience clinical samples were collected between January and February 2022 from individuals suspected of SARS-CoV-2 infection and were included in our genomic surveillance framework for real-time monitoring of circulating SARS-CoV-2 variants in the region . NasophaSamples were chosen for sequencing based on a Ct value ≤30) and the availability of epidemiological metadata, including the date of sample collection, sex, age, and municipality of residence. The SARS-CoV-2 genomic libraries were prepared using nanopore sequencing. Complementary DNA (cDNA) synthesis was performed using the SuperScript IV Reverse Transcriptase kit  following the manufacturer’s instructions. The generated cDNA underwent multiplex PCR sequencing using the Q5 High-Fidelity Hot-Start DNA Polymerase  and a set of specific primers designed by the ARTIC Network for sequencing the complete SARS-CoV-2 genome (Artic Network version 3) . PCR conditions have been previously reported [0 and theThe raw files from Oxford Nanopore sequencing were basecalled using Guppy v3.4.5, and barcode demultiplexing was conducted using qcat. Consensus sequences were then generated through de novo assembly using Genome Detective .https://github.com/andersonbrito/subsampler (accessed on 10 July 2023), which enabled us to perform random subsampling of sequences per country based on case counts over the study period. By doing so, we ensured that our samples were geographically, temporally, and epidemiologically representative. Furthermore, the subsampling within this scheme was conducted using a baseline function, which allowed us to determine the proportion of cases we aimed to sample. This process was carefully designed to maintain the overall characteristics and diversity of the data while minimizing potential biases. All sequences were aligned using the ViralMSA tool [−4 nucleotide substitutions per site per year, after removing outlier sequences.Lineage assignment was conducted using the Phylogenetic Assignment of Named Global Outbreak Lineages tool (PANGOLIN) . The newMSA tool  and the MSA tool . To obtahttps://github.com/wcota/COVID19br (accessed on 10 July 2023).Data from weekly notified cases of infection, deaths, and hospitalization by SARS-CoV-2 in the state of Mato Grosso do Sul were supplied by the Brazilian Ministry of Health, as made available by the COVIDA network at The SARS-CoV-2 epidemic in the state of Mato Grosso do Sul consisted of four distinct main waves , resultiThe second wave, which occurred from October 2020 to December 2020, was driven by the emergence and rapid spread of the P.2 (Zeta) variant under monitoring (VUM). In contrast, the third wave (December 2020 to May 2021) was primarily caused by the introduction of the Gamma (P.1) variant of concern (VOC), resulting in a significant increase in the number of reported cases and deaths in the country . HoweverFurthermore, our analysis of the total number of cases, deaths, and COVID-19-related hospitalizations revealed that the age group between 20 and 59 years bore the highest disease burden from February to May 2021. This spike in cases coincided with the circulation of the Gamma variant, which overwhelmed healthcare facilities at both the national and regional levels, primarily impacting the susceptible population.In order to retrospectively reconstruct the transmission dynamic of the Omicron variant in the state of Mato Grosso do Sul, a total of 69 near-full genome sequences were obtained from SARS-CoV-2 RT-qPCR positive samples as part of this study. The sequencing spanned from January to February 2022, and samples were collected from 10 distinct cities across the state A.These samples comprised 41 females and 28 males , with a https://www.gisaid.org/) up to 2 June 2023, revealed that the newly obtained genomes belong to different SARS-CoV-2 Omicron BA.1 sublineages  for library preparation. The average PCR cycle threshold (Ct) value for positive samples was 20.75 (range: 10 to 30). Sequences had a median genome coverage of 94% (range: 72 to 99.99), with samples that had lower Ct values generally exhibiting higher average genome coverage B. Detaillineages D, which lineages D. This plineages .Genomic surveillance is of pivotal importance in monitoring SARS-CoV-2 variants and informing public health responses. Variants of concern (VOCs) have had a significant impact on the severity of COVID-19, therapeutic approaches, and vaccination efforts ,15,16,17To assess the impact of the Omicron variant in Mato Grosso do Sul, a state located in the Midwest region of Brazil, we conducted on-site training in genomic surveillance in collaboration with the state’s Public Health Laboratory. Through this collaboration, we were able to generate 69 newly SARS-CoV-2 complete genome sequences. Our analysis revealed four waves of the SARS-CoV-2 epidemic in the state, with each wave characterized by the circulation and replacement of different viral strains ,17. ConsOur data demonstrated that the emergence of the Omicron variant coincided with the fourth major wave, exhibiting a distinct pattern of a rapid peak followed by a swift decline . This trGenomic monitoring in our study additionally identified distinct Omicron sublineages , indicatIn conclusion, this study emphasizes the significance of genomic monitoring in comprehending the transmission dynamics of emerging variants. Further advancement in the field of genomic surveillance necessitates investigation in several areas and should focus on long-term genomic monitoring to track the evolutionary trajectory and potential changes in viral genetic characteristics. Comparative genomic analyses across different regions and countries will also be crucial to identify geographic-specific patterns and inform targeted public health interventions. Exploring the role of host genetic factors and their interplay with viral evolution will further enhance our understanding of susceptibility, disease severity, and vaccine response. Lastly, expanding genomic surveillance to include animal hosts and environmental samples in a One Health approach can facilitate early detection and response to zoonotic transmission.


Fiber waviness and voids may be produced in thick composites due to improper manufacturing conditions and consequently pose a risk of structural failure. A proof-of-concept solution for imaging fiber waviness in thick porous composites was proposed from both numerical and experimental studies, via calculating ultrasound non-reciprocity along different wave paths in a sensing network constructed by two phased array probes. Time-frequency analyses were conducted to reveal the cause of ultrasound non-reciprocity in wavy composites. Subsequently, the number of elements in the probes and excitation voltages was determined for fiber waviness imaging using the ultrasound non-reciprocity with a probability-based diagnostic algorithm. The fiber angle gradient was observed to cause ultrasound non-reciprocity and fiber waviness in the thick wavy composites were successfully imaged regardless of presence of voids. This study proposes a new feature for the ultrasonic imaging of fiber waviness and is expected to contribute to processing improvement in thick composites without prior knowledge of material anisotropy. Thick carbon-fiber-reinforced plastic (CFRP) components have been increasingly adopted in aerospace structures due to their excellent static and fatigue properties . The keyNon-destructive testing (NDT) is prevailingly used for the quality verification and damage evaluation of composite structures after manufacturing and during service ,5. X-rayOn the other hand, tracing fiber orientations in composites using ultrasound features has recently become a hot topic ,21,22,23To sum up, the abovementioned UT technologies are mainly aimed at single-type defect inspection and cannot achieve the characterization and differentiation of mixed-type defects in thick CFRP. Fiber waviness  and thick resin layers may coexist in thick composites . Both deIn this manuscript, simulation and experiment setups for imaging diverse defects in thick composites using two phased array probes are first introduced. Subsequently, ultrasound propagation in non-wavy and wavy composites with 2 mm-diameter voids is investigated numerically. To gain an insight into the generation mechanism of ultrasound non-reciprocity, the time frequency spectra of the first-arrival transmitted waves in the thick composites with different microstructures are compared when the wave propagation directions are reserved. Subsequently, the time-of-flight difference (24s) and wavy composites , were fabricated using carbon-fiber-reinforced epoxy prepreg (T300-USN15000-7901-33%). The samples were cured for 2 h at 120 °C in a vacuum hot press machine. After curing, typical layer thickness for the non-wavy composites was measured as 0.125 mm. Half steel cylinders with diameters of 6 mm were placed on the layered prepreg during curing to generate out-of-plane fiber waviness ® 1.30.11.0) with accurately duplicated fiber orientations  of the numerical model in ® v3.12.0) developed by the University of Nottingham and exported to OnScale® with the desired simulation settings.Four types of numerical models, i.e., non-wavy and wavy composites with/without voids, were built, and the models of the porous non-wavy and wavy composites are shown in 3) along with a compliance matrix . The resin layers were defined as isotropic linear elastic material using density (1301 kg/m3), bulk modulus (4.67 GPa) and Poisson’s ratio (0.37). An explicit solver was used to calculate wave responses.A structural mesh with low-order quadrilateral elements was used in the 2D simulation. A Ricker wave with a center frequency of 6 MHz was adopted for the excitation. The excitation signal was generated by applying surface pressure at the center of the array elements, and the receiving signals were extracted as the average values of the surface pressure of a specific array element in the phased array probes. Considering the influence of thick resin layers (>10 Two phased array probes (Doppler 5L64-0.6·10) with a nominal center frequency of 5 MHz were connected to a phased array system (PeakNDT LTPA 128/64PR) using a customized splitter, as shown in To avoid boundary reflections, the time of flight of the transmitted ultrasound was calculated using the propagation time of the first-arrival waves. Ultrasound non-reciprocity was quantified by Here, To gain insight into the generation mechanisms of ultrasound non-reciprocity in composites, the To validate the effectiveness of the senor network built by the two phased array probes for the inspection of fiber waviness, simulated ultrasound signals propagating along different directions in the non-wavy and wavy composites without voids are shown in From The simulated To validate the numerical predictions, the non-wavy composites without and with a 2 mm-diameter SDH were inspected experimentally. Firstly, the influence of excitation voltages on the ultrasound non-reciprocity was investigated. The experimental Simulated To further investigate the effectiveness of the proposed method for imaging fiber waviness in thick wavy composites with large voids, as shown in To validate the numerical predictions as shown in The experimental Ultrasonic images of large voids with a 2 mm diameter in traditional B-scans may be distorted by fiber waviness and masked by reflections from the thick resin layers near the surface. The presence of fiber waviness cannot be determined in thick composites with diverse defects using traditional pulse echo or through transmission testing.Fiber waviness introduces difference in the transmission coefficients of ultrasound under distinct frequencies when the propagation direction is reversed. Due to dispersion behaviors of ultrasound in composites, ultrasound non-reciprocity in terms of group velocity generates in the wavy composites. Such ultrasound non-reciprocity is sensitive to fiber angle gradient caused by fiber waviness.The proposed probability-based diagnostic algorithm on ultrasound non-reciprocity successfully imaged and identified fiber waviness in thick wavy composites regardless of the presence of voids. With the combination of transmitted and reflected wave energy, the proposed method can improve the reliability of the ultrasonic characterization of diverse defects in the thick composites.In this manuscript, a novel method for imaging fiber waviness in thick composites using ultrasound non-reciprocity with a probability-based diagnostic algorithm was proposed. Conclusions can be drawn from the simulation and experiment as below:As a proof-of-concept study, the proposed method was proven to be capable of imaging fiber waviness in thick wavy composites. However, theoretical models are required to establish a quantitative relationship between the ultrasound non-reciprocity and severity of fiber waviness. Therefore, the coefficient γ for the quantitative evaluation of fiber waviness using the probability-based ultrasound non-reciprocity can be optimized. Furthermore, future work will be devoted to signal processing to improve the sensitivity of the proposed method for fiber waviness at small deviation angles.