Coronavirus disease 2019 (COVID-19) causes psychological distress and can have a negative impact on the general mental health and rehabilitation in affected patients under currently implemented isolation guidelines. Auricular point pressure (APP) as well-established technique in traditional Chinese medicine may help to relieve sleep disturbance and anxiety in COVID-19 patients. n = 84). They were strictly isolated on specific wards at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei. The retrospective cohort study design included two groups. Group A patients were treated with an auricular point pressure (APP) in addition to standard intensive care medicine while Group B participants (No-APP) received routine nursing measures alone. Treatment outcome was measured using the St. Mary's Hospital Sleep Questionnaire (SMH) Score and the 7-Item Generalized Anxiety Disorder Scale (GAD-7). Both scores were measured in each patient at baseline and on the discharge day.  During the early phase of the epidemic/pandemic, patients were enrolled in this study (02/2020 until 03/2020 P < 0.01). APP-treated patients demonstrated lower GAD-7 scores than No-APP controls (P < 0.01). Further, no significant differences in safety or adverse events between the APP and No-APP groups were observed.  The SMH score and sleep status changed in APP patients at the end of the treatment period when compared with No-APP patients ( The results from our snapshot study during the early phase of the SARS-CoV-2 epidemic/pandemic suggest that auricular point pressure could be a simple and effective tool to relieve insomnia and situational anxiety in hospitalized patients suffering from COVID-19 and kept under disconcerting conditions of isolation. COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It spread out rapidly worldwide which started in late December 2019 . As a reRigorous isolation with direct contact only to almost not identifiable medical and nursing staff under personal protective equipment (PPE) may trigger additional psychological distress in COVID-19 patients suffering from respiratory and other serious health problems. Therefore, recovery from physical and psychological limitations seems to be negatively influenced through needed quarantining and contact restrictions during the acute phase of COVID-19 as well as the following rehabilitation phase , 7. The Vaccaria segetalis) over the appropriate acupressure point on the ears; the seed is held in place with an adhesive material, thereby stimulating the meridians. This influences the release of neurotransmitters from neurons and regulates functions of the endocrine system and viscera. As a result, it can reduce symptoms of discomfort and can help to successfully treat several diseases [Traditional Chinese medicine (TCM) has been used for more than 2,000 years and plays an important role alongside of contemporary medicine in China . TCM hasdiseases .Despite the benefits of APP, no clinical trials have been documented so far to evaluate its effects in patients with COVID-19. Therefore, this study was performed to investigate the safety and efficacy of APP in patients with COVID-19.A retrospective cohort study was conducted at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei Province with a total of 84 patients with COVID-19  that participated in this study after confirmed consent (02/2020 until 03/2020). Eligible patients were assigned to either the APP group (Group A: APP plus regular nursing) or the control group  on their own will. Patients in Group A received APP in accordance with evidence-based principles. The patients and researchers were not blinded to treatment allocation.Vaccaria segetalis seeds were placed with a piece of tape on the following ear acupoints until the patient felt aching, numbness, distention, or pain: Fei (CO14), Jiaogan (AH6a), Shenmen (TF4), Pizhixia (AT4), and Neifenmi (TF2). They remained attached on the ear and were pressed by the patient for one minute at 4- to 6-hour intervals. Patients were also instructed to press the point 15–30 min before bedtime. The seeds were replaced and added to the other ear at 3-day intervals.Prior to the procedure, the TCM nurses thoroughly washed their hands and disinfected each acupressure and then dried. The main endpoints investigated were symptoms of depression, anxiety, insomnia, and distress for all participants. The 7-Item Generalized Anxiety Disorder (GAD-7) scale  and the St. Mary's Hospital (SMH) Sleep Questionnaire were used to assess the severity of anxiety and sleep symptoms, respectively. The endpoints were measured using the Chinese versions of these validated measurement tools.The study was undertaken in compliance with the principles of the Declaration of Helsinki. Ethics approval was reviewed and approved by the hospital's Human Research Ethics Committee (no. ZE2020-032-01). The clinical trial has been publicly registered in the National Health Insurance Information Platform for Medical Research Registration and Recording Information System (no. MR-44-20-002619) on March 14, 2020.The trial data and statistical analysis were handled by the author to maintain patient confidentiality; collected data were stored in a locker in the private office of the author.The participants were chosen based on their clinical characteristics and the presence of laboratory-confirmed COVID-19, based on the “Pneumonia Diagnosis and Treatment Protocol for Novel Coronavirus (SARS-CoV-2) Infected Pneumonia”  . Prior tThe inclusion criteria were as follows: (1) diagnosis of pneumonia based on clinical manifestations and abnormal findings in chest X-rays or computed tomography scans and (2) confirmation of COVID-19 by high-throughput sequencing or real-time reverse transcriptase polymerase chain reaction assays from nasal and pharyngeal swab specimens . The excVaccaria segetalis seed was purchased from Shanghai Taicheng Tech & Development Co., Ltd. .The During enrollment, participants' demographic data were collected regarding sex, age, and dependence on assistance from an attendant. Study outcome measures were assessed from baseline until the day of discharge  .The primary outcome parameters were sleep condition events associated with SMH score from baseline to follow-up. The SMH is a systematic inquiry into a patient's sleep experience and comprises items of demonstrable reliability , 15. Theɑ = 0.911). GAD-7 descriptors were translated into Chinese for this study.The prespecified secondary outcome was the GAD-7 score. The GAD-7 is a one-dimensional instrument designed to detect symptoms of generalized anxiety disorder . The GADDuring the trial, patients in both groups were visited at baseline and on the day of discharge following the first treatment. All patients completed the SMH and GAD-7 assessment .χ2 test or Fisher's exact test was used to compare percentages between groups. Data were carefully reviewed and confirmed by an experienced physician team to ensure their accuracy.In this study, continuous variables were expressed as means and standard deviations or standard errors of the mean, as specified. They were analyzed together with summarized categorical data as frequencies or percentages. The statistical analyses were performed using IBM SPSS Statistics, version 22.0 . The general descriptive characteristics were calculated, including baseline patient characteristics and outcomes. The primary outcome was based on the GAD-7 for anxiety. Secondary endpoints were the SMH for the patients' sleep conditions. The In this study, the safety profiles of the study interventions in both groups were assessed by the number of AEs reported during the treatment period. When an AE occurred, the investigator evaluated the outcome and its relevance to the study. Based on its relevance, a decision was made regarding continued observation.n = 66) or control group (Group B: n = 18)  . Baselin n = 18) . The meaP < 0.05) (n = 38) a score lower than 4, while in the No-APP group eight patients still demonstrated scores between 5 and 9 and one patient a score higher than 10. This trend clearly showed for the APP group a better GAD-7 outcome score (Both groups showed significantly lower GAD-7 scores compared to baseline while intergroup comparison demonstrated for the APP group patients a significantly lower GAD-7 score (0.5 ± 0.7) compared with the control group  . Analysime score . Moreoveme score .P < 0.01) than patients in the control group at their respective study endpoints (n ≤ 7) and when the disease lasted over 14 days demonstrated lower SMH scores (P < 0.05)  .No serious adverse events in the treatment group and no significant differences in safety or adverse events (AE) between the APP and the control group were observed during the study. Most patients tolerated APP well.The COVID-19 pandemic has profoundly affected the health and livelihood of millions of people worldwide at an unprecedented scale and speed. Fortunately, vaccination programs have most recently been started in many countries after tremendous efforts in vaccine development within the last 12 months since the outbreak in 2020. This gives hope and encourages people to become actively immunized with one of the meanwhile available vaccines against SARS-CoV-2 for antibody-based protection against severe courses of COVID-19 . HoweverAuricular points refer to acupoints distributed on the auricle, and auricular point pressure (APP) represents a subdiscipline of both acupuncture and TCM. APP can stimulate the meridians because it applies pressure to an acupoint. Each of the acupoints reflect the physiological and pathological condition of its corresponding body part and must be stimulated by pressure or by a needle to regulate the dysfunction in that body part . SpecifiVaccaria segetalis seed  over the appropriate acupressure point on the ears. Wangbuliuxing, the seed of Vaccaria segetalis, is native to temperate zones in Asia, Africa, and Europe. It has been used for the treatment of amenorrhea, mastitis, and urinary diseases in TCM [However, the desired effect is not simply elicited by manual pressure. APP consists of the application of pressure to specific locations on the ear. The intervention by auricular acupressure involves the placement of a s in TCM . The mais in TCM . Additios in TCM .In addition, APP can also be achieved manually  with an acupuncture needle, laser, or a magnet. All of this can be used as complementary treatment and generally contribute to improvement of symptoms and reduction of exacerbation. It influences the release of neurotransmitters which transmit signals along neurons, thereby regulating the function of endocrine organs and the viscera. These neuroregulatory changes can reduce symptoms of discomfort and cure several diseases , 26.Previous studies have shown that this alternative, a nonpharmacological APP treatment, can relieve a variety of distressing symptoms including dyspnea , amenorrOur findings from a pilot cohort study have shown that auricular acupressure could reduce anxiety and improve sleep quality in patients with COVID-19. The results are consistent with data from previous research , 33 and The design process was rigorous and the trained medical staff involved in the research strictly followed the standard operating procedures. However, this pilot study also had several limitations. First, it was limited in sample size; given the COVID-19 pandemic, a blinded or sham control group could not be included. Second, the study was carried out within a short treatment period of 10 days, with assessment only on two occasions at the beginning and at the end of the treatment interval, and almost equally important, the study lacked a longitudinal follow-up. More precisely, the long-term psychological changes of patients in this population are worth of further investigation. Third, with SMH and GAD-7 scores, it is only to a limited extent possible to provide a reasonably accurate assessment of the severity and impact of side effects experienced by patients with COVID-19. Nevertheless, our data represent a snapshot that demands for larger randomized studies with more longitudinal assessment of the study population to reinforce our findings.In conclusion, our results suggest that auricular point pressure could be a promising additional tool in the multimodal treatment for improving outcome in patients with COVID-19. Patients in the APP treatment group showed considerable symptom relief (sleep disturbances and anxiety) and improved quality of life, as indicated by the SMH and GAD-7 scores. Moreover, our results demonstrated APP as a safe and easily applicable treatment in patients with COVID-19. Further clinical studies are necessary to more comprehensively evaluate the application of APP in these patients over longer time periods.


MR-guided adaptive radiotherapy (MRgART) provides opportunities to benefit patients through enhanced use of advanced imaging during treatment for many patients with various cancer treatment sites. This novel technology presents many new challenges which vary based on anatomic treatment location, technique, and potential changes of both tumor and normal tissue during treatment. When introducing new treatment sites, considerations regarding appropriate patient selection, treatment planning, immobilization, and plan-adaption criteria must be thoroughly explored to ensure adequate treatments are performed. This paper presents an institution’s experience in developing a MRgART program for a 1.5T MR-linac for the first 234 patients. The paper suggests practical treatment workflows and considerations for treating with MRgART at different anatomical sites, including imaging guidelines, patient immobilization, adaptive workflows, and utilization of bolus. After over a decade of development, the integration of magnetic resonance (MR) imaging and linear accelerators has been realized within the context of clinical radiation therapy ,3,4,5,6.The Elekta Unity MR-linac  used in this body of work consists of a Philips 1.5T MR imaging system  coupled with a single-energy linear accelerator capable of producing a 7-megavolt (MV) flattening filter-free (FFF) photon beam with a source-axis distance (SAD) of 143.5 cm and a nominal dose rate of 425 MU/min at isocenter .The 1.5T MRI can perform imaging prior to treatment for registration and setup, during treatment planning or treatment, and after treatment is complete. Additionally, for all sites excluding brain, live motion-monitoring cine imaging of the cardinal planes is available at 5 frames per second (FPS).This MR-linac is capable of performing adaptive radiotherapy using two primary workflows: adapt-to-position (ATP) and adapt-to-shape (ATS). The ATP workflow is a standard image-guided radiotherapy (IGRT-based) workflow and is able to be quickly executed but restricted to a rigid translational registration and a limited optimizer that works to strictly reproduce dose-volume histogram (DVH) characteristics of the reference plan, while the latter (ATS) permits recontouring and access to the full treatment-planning system optimizer.The adaptive radiotherapy program is located at an academic medical center in the United States that includes 8 subspecialized radiation oncologists. The MRgART program is overseen by 5 medical physicists and planning is performed by 2 dosimetrists with adaptive-radiotherapy-specific Monaco training. Six radiation therapists, dually certified in radiation therapy and MRI, perform patient screening prior to MR simulation, setup, and delivery to ensure MR safety procedures are followed and operate the MRI portion of treatment. They also perform an integral role during the MRI portion of pretreatment patient simulation, including performing navigator-triggered imaging and patient compression as a method of motion management. The therapists ensure that vital information is communicated between the physicists and attending radiation oncologists between treatments, as their schedule provides a consistent presence throughout a treatment course. The facility has staffed a 3T MR simulator since 2005 and has a history of dual-certified staff for MR-based procedures.Patients were selected based on physician perception that they would benefit from the improved soft-tissue contrast, motion monitoring, daily adaption, or any combination of the three. Common contraindications for treatment on the 1.5T MR-linac included the presence of ferromagnetic implants or non-MR-compatible devices, severe claustrophobia, restrictively large body habitus exceeding the receiver coil bridge or bore size, or inability to hold the immobilized position for the entire treatment duration. Patients whose treatment target exceeded the field size limits of the 1.5T MR-linac system were also excluded.From 22 May 2019 to 1 December 2021, 234 patients received treatment using MRgRT, and of these patients 121 were treated using a stereotactic body radiotherapy (SBRT) technique. For these patients, 3242 fractions were delivered with 594 (18.3%) following the adapt-to-shape (ATS) workflow and 2648 (81.6%) with the adapt-to-position (ATP) workflow. The most commonly treated site was prostate (23%) with oligomets (14%), liver (13%), and pancreas (10%) being the next most common sites of treatment. The total distribution of treatment sites and patients treated with ATP or with at least one ATS fraction can be found in The planning tools provided by the Monaco treatment-planning system in conjunction with the daily MRI-guided adaptive treatment planning. Briefly, pretreatment planning , referred to as reference planning, is identical to traditional radiation-treatment-planning workflows (detailed in the following section). On the day of treatment delivery, a new MRI is obtained and a decision is made while evaluating the daily MR image registration to select the adapt-to-position or adapt-to-shape MRgART workflows . In our Prior to the first treatment, an initial reference treatment plan based on simulation imaging is created for each patient. Patient simulation consists of both CT (or CT/positron emission tomography (PET)) and MRI components with MRIs acquired on a 3T Siemens Magnetom Trio  and CTs or CT/PET acquired with a Siemens Biograph 40 PET/CT scanner. MRIs are acquired using multiple sequences that aid in OAR and target delineation. The simulation MRI sequences can also be used to determine the scan protocol best suited for registration during daily imaging. For MRI simulation, T1 and T2 scans are acquired, with additional scans acquired based on treatment location, use of contrast, or per the attending physician’s request. During this imaging, the patient is observed for anxiety and comfort in the immobilization devices that may rarely contraindicate daily treatment on a closed-bore system. Due to patients not being simulated on the MR-linac, which provides more treatment time on the machine, clearance for the imaging coil bridge is also tested using an in-house-developed acrylic replica of the MR-linac anterior coil to ensure that there will be adequate clearance during treatment . As one Treatment planning is performed using the Monaco treatment-planning system V5.51.10 by dosimetrists trained in MRgRT planning. The MRI, PET, and CT images are registered, and the fusion used for target and OAR delineation. Information for the bulk electron-density overrides used for adapt-to-shape (ATS) planning are extracted from the contoured CT structures, taking into consideration the use of contrast or artifacts which may distort the electron-density information. The layering order of the electron-density assignments are of significant importance, as these values will automatically propagate to daily MRI images during all ATS workflows. In general, in our clinical practice, organs with contrast are overridden to electron-density values derived from the average of a similar cohort of patients.Templates with arrangements of 9 to 11 beams are commonly used for plan generation. Each beam arrangement is selected to avoid the high-density couch angles located approximately between 110°–135° and 230°–255° and the cryostat pipe at 13° . The iniOnce an acceptable plan is created, a secondary dose calculation is performed using a version of RadCalc V6.3  modified to model the unique system geometry. A data-transfer integrity check, comparing the plan parameters between the treatment-planning system (TPS) and Mosaiq record and verify system, is also completed using RadCalc . AlthougThe pretreatment daily MRI is registered to the image set used for planning, most commonly a CT scan at our institution, and evaluated by the medical physicist to determine whether the ATP or ATS workflow is needed. Common parameters evaluated include patient alignment to the reference images, changes in tumor volume, image quality of MRI, and organ location and size. Factors influencing the decision can include the use of larger planning target volume (PTV) and planning organ-at-risk volume (PRV) margins which are used when intrafraction motion or organ expansion is expected. If patient anatomy sufficiently agrees with the simulation scans, the ATP workflow is performed. Of the available optimization options, only the optimize-weights-and-shapes method is used due to the improved plan quality relative to the faster optimization options . The finWhen patient anatomy significantly varies relative to the reference plan or a dosimetric objective is difficult to achieve with the ATP optimization method, the ATS workflow is used. The institutional workflow for ATS involves recontouring of the targets by the attending physician and verifying OAR contours that have been recontoured or deformed by the physicist to the current patient anatomy. The plan is then generated, and bulk density overrides are verified. Due to the longer time required for the ATS workflow, a verification MRI is acquired during the optimization phase to ensure the patient has not moved and organs remain in a similar location . At thisFor both ATP and ATS treatment options, data-transfer integrity and secondary dosimetric calculations are performed using RadCalc for each fraction . AdditioTargets and OARs located in the abdomen can benefit from MRgRT due to the excellent soft-tissue contrast to distinguish the organs clearly and the ability to adapt target and OAR volumes daily. However, targets and OARs in the abdomen may be highly mobile with daily variations in position, while targets located near the diaphragm  may also be influenced by respiratory motion .As seen in During planning, the exhale breath-hold scan is used as the primary dataset and the 4DCT  scans are used to create an ITV using Boolean operations. This margin structure is then converted to a rigid structure to preserve the motion information which will not be available during the pretreatment navigator-triggered MRI and can be used for PTV generation. Currently, 4D MRI sequences are not part of the standard imaging sequences provided by the vendors. When abdominal compression is used, a pretreatment cine MRI is acquired, and the superior/inferior diaphragm motion is assessed and compared to the motion recorded on the day of simulation. If the diaphragm-motion difference between treatment and simulation is >5mm, the physicist is paged, and additional compression may be applied. Once the diaphragm-motion difference is ≤5 mm, a standard abdominal treatment workflow is used, starting with the acquisition of a navigator-triggered MRI scan which acquires the MRI only at the end expiration-breathing phase ,18. The This clinic has delivered 93 fractions to 19 patients using this abdominal compression protocol. Superior/inferior motion of the diaphragm was reduced by 10.6 ± 4.6 mm using abdominal compression for these patients. During treatment, motion was evaluated using a cine MRI during treatment to verify similar conditions to simulation. The average difference in the diaphragm motion between simulation and treatment was 1.3 ± 1.6 mm with a maximum of 6 mm across all fractions.Patients with head and neck treatments may benefit from adaptive radiotherapy for multiple reasons. The ability to easily visualize and recontour critical organs and targets on MRI allow for precise contouring, alignment, and review of the dose distribution. While immobilization for these treatments includes a head and shoulder mask and a custom acrylic baseplate , flexionAdditional considerations of the acrylic baseplate must be considered during treatment planning due to the baseplate not being visible. Currently, the Monaco treatment planning system only allows for a single couch structure, so a unique workflow has been developed to ensure proper placement of the treatment couch with respect to the acrylic baseplate and patient external surface. During generation of the reference treatment plan, the acrylic baseplate and patient contour are separately contoured and then combined as a margin structure to create the external contour. Creating the external surface as a margin structure allows the patient contour to be deformed to changing patient anatomy while including the electron density of the acrylic baseplate in the dose calculation. Failure to complete this workflow will result in the couch top being placed such that it overlaps with the acrylic baseplate, which is not representative of the actual treatment setup.The clinical workflow at our institution includes the use of offline adaptive plans for head and neck cases. Current time constraints for online adaptive radiotherapy for head and neck treatments due to the extensive recontouring can make online adaptions difficult . For patFor the 15 patients treated for head and neck cancer, 27 offline adaptions have been performed and 8 online adaptions have been performed. One patient was adapted a total of 8 times offline to account for both tumor regression and variations of patient anatomy, shown in Multiple extremity sites have been treated including patients with sarcomas of the thigh, foot, and hand. Patients with extremity targets selected for treatment using MRgART typically have lesions that are either easily visualized on daily MRI or the variations in daily position, swelling, and tumor regression must be accounted for with daily plan adaptions. Immobilization for these patients typically includes an indexed Vac-Lok and carefully considered positioning to ensure the extremity is as close to the center of the bore as possible. Such positioning maximized the useable field size and provided the best image quality.Many of the extremities treated are shallow targets requiring superficial coverage, traditionally achieved using bolus. Not all bolus materials are visible during MRI imaging, and unexpected air gaps significantly reduce skin dose during delivery . ClinicaBrain treatments benefit from MRgART due to the excellent soft-tissue contrast and visualization of neurological structures utilizing different imaging sequences. Immobilization for brain treatments is performed using an acrylic baseplate similar to the one shown in Practically, this is accomplished by imaging with a T2 FLAIR pretreatment-imaging sequence for the initial course, allowing for edema visualization and adaption as the edema volume changes, followed by T1 imaging for the sequential boost to the high-dose target . PatientDue to the novel nature of adaptive therapy and MRgRT at our institution, the program is constantly improving and expanding. The speed of these developments across all facets of the treatment workflow warrant maintaining current knowledge and diligent attention to workflows. Second-check algorithms performing Monte Carlo calculations or incorporating asymmetric field shapes are being developed by multiple vendors in the field, providing more accurate validations of the TPS. Improvements from the vendor demonstrate potential to improve patient throughput and treatment workflows through AI-contouring tools, gated delivery, improved optimization algorithms, and the potential for helical treatments ,23,24. WWhile ATS workflows will likely remain a task of the medical physicist until these tools are further developed, the eventual goal of transitioning all ATP treatments to radiation-therapist-led workflow is attainable with the current tools and additional training. Additional roles have already been transitioned to the radiation therapists under the supervision of the medical physicist, including initial registration, second-check calculations, and data-transfer integrity. With more time and development of workflows, a complete transition and training is anticipated in the future.In summary, modern MRgART adaptive radiotherapy programs require a team-based approach from physicists, physicians, dosimetrists, and therapists to ensure safe and effective daily treatments. This manuscript outlines several of the key aspects to treatment planning and delivery for a number of sites but is not meant to represent an exhaustive list. Many of the recommendations made are a result of weekly meetings with the MR-linac team and the associated discussions of individual cases. A methodical and thorough approach to introducing additional treatment sites or techniques should include similar discussions with a comprehensive group representing all aspects of the MRgART team. The additional complexities of working in the MR environment with adaptive radiotherapy present clinical challenges, but when addressed properly present large opportunity for improved patient care.


How best to prioritise COVID-19 vaccination within and between countries has been a public health and an ethical challenge for decision-makers globally. We reviewed epidemiological and economic modelling evidence on population priority groups to minimise COVID-19 mortality, transmission, and morbidity outcomes.We searched the National Institute of Health iSearch COVID-19 Portfolio (a database of peer-reviewed and pre-print articles), Econlit, the Centre for Economic Policy Research, and the National Bureau of Economic Research for mathematical modelling studies evaluating the impact of prioritising COVID-19 vaccination to population target groups. The first search was conducted on March 3, 2021, and an updated search on the LMIC literature was conducted from March 3, 2021, to September 24, 2021. We narratively synthesised the main study conclusions on prioritisation and the conditions under which the conclusions changed.The initial search identified 1820 studies and 36 studies met the inclusion criteria. The updated search on LMIC literature identified 7 more studies. 43 studies in total were narratively synthesised. 74% of studies described outcomes in high-income countries (single and multi-country). We found that for countries seeking to minimise deaths, prioritising vaccination of senior adults was the optimal strategy and for countries seeking to minimise cases the young were prioritised. There were several exceptions to the main conclusion, notably that reductions in deaths could be increased if groups at high risk of both transmission and death could be further identified. Findings were also sensitive to the level of vaccine coverage.The evidence supports WHO SAGE recommendations on COVID-19 vaccine prioritisation. There is, however, an evidence gap on optimal prioritisation for low- and middle-income countries, studies that included an economic evaluation, and studies that explore prioritisation strategies if the aim is to reduce overall health burden including morbidity.The online version contains supplementary material available at 10.1186/s12916-021-02190-3. As of September 2021, over 6 billion vaccine doses have been administered, but vaccines are still in limited supply in many countries . We . We 4]. We included English language published or pre-print studies that used mathematical modelling to assess the impact of prioritising population target groups (either within or between countries) for COVID-19 vaccination on mortality, health , health care , and/or economic (e.g. costs and cost-effectiveness) outcomes. We excluded studies which did not use a mathematical model to project the impact of COVID-19 vaccination, where none of the parameters were determined by empirical data , or which modelled vaccination outcomes within a clinical trial or a within-country small local setting, such as a care home, rather than nation or district wide allocation. For the updated search for LMIC literature, we applied an additional criterion of excluding HIC studies.Two researchers independently screened titles and abstracts during the first round of screening. During the second round, three researchers independently screened titles/abstracts and full-text articles. All studies were screened by at least two reviewers, where there were disagreements about inclusion these were resolved in discussion with a fourth researcher. Three groups of two researchers each independently extracted the data from the included studies, with at least two groups reviewing each study. Discordant entries between the sets of extraction sheets were resolved by discussion between the groups. Data were recorded in Microsoft Excel files summarising the policy objectives, outcomes, characteristics of the studies, the study conclusions and the conditions under which the conclusions changed, i.e., sensitivity analyses . We therefore extracted data and organised our results tables by the objective used. Some studies used two objectives to inform prioritisation (for example cases and deaths). In these instances, we extracted and synthesised both sets of results. A full list of outcomes modelled in the included studies can be found in Table Studies had different combinations of comparators, so we present results specifying the full range of comparator populations assessed. Study setting was categorised as high-income (HIC), upper middle-income (UMIC), lower-middle income (LMIC), low income (LIC), multi-region, or not specified, using World Bank classifications for 2021 . We extrIn the first search, our database search returned 2279 studies. After the removal of 459 duplicates, 1820 records were included in the title and abstract screening. After title and abstract screening, 55 studies remained for full-text screening. After assessing the full text of the 55 studies for eligibility, 36 studies were included in the systematic review. After updating the search to look for studies set in LMIC countries having identified this as the predominant gap in the literature, 7 more studies were included  minimised deaths  investigated optimal vaccine prioritisation strategies to minimise COVID-19 cases. Of these, seven studies recommended young and middle-aged adults . These studies reached the same conclusions as the HIC studies i.e. studies minimising deaths recommended prioritising seniors, while those minimising cases recommended prioritising high transmission groups. The exception was one study from Thailand on minimising cases which recommended prioritising high transmission groups to minimise deaths [Five of the included articles were single-country studies modelling LMIC settings , 22, 46.33e deaths .,20,There were also five multi-country studies which modelled LMIC settings ,20,24 One study also considered prioritisation between countries, in addition to within countries. This study made recommendations on global vaccine allocation strategies to optimise different health objectives . The aut40 out of 43 (93%) studies included a sensitivity analysis  as the optimal strategy, unless there are exceptional cases where specific non-age-related high-risk groups or very highly networked individuals can be identified and prioritised. The difference in deaths averted can be large between depending on the strategies, for example in this study, a symptom-blocking vaccine with 50% uptake prioritising seniors and high-risk groups averted 17,000 more deaths than an unprioritised campaign . For couWhile in principle prioritising highly socially connected groups may be optimal to reduce mortality, it could prove difficult in practice to identify these groups, especially when their definition and means of identification are only vaguely defined , 37, 38.A study in Thailand examined how vaccines may be prioritised in a low-incidence setting , findingThere was only one study modelling inter-country allocation of vaccines , despiteThere were two studies modelling allocation of vaccines between geographical areas within the same country , 46. OneOnly one study incorporated the impact of variants of concern on vaccination prioritisation , possiblOur review found that the optimal prioritisation strategy to pursue depends on the public health objective(s) of the decision-maker, with different conclusions depending on whether the objective is reducing cases or reducing mortality , 38. TheThe WHO SAGE value framework for the allocation and prioritisation of vaccines proposed 6 principles as the ethical basis of decisions on vaccine prioritisation: the promotion of human well-being, equal respect, global equity, national equity, reciprocity, and legitimacy . Within Only one study considered within-country equity (such as prioritising populations that have suffered disproportionately from COVID-19 because of their socioeconomic status) . We alsoOur findings are limited by several methodological issues. By limiting our search to English language studies, we may have missed relevant studies, particularly in low- and middle-income countries. Much of this literature is pre-print studies which are not peer-reviewed, so the quality of the evidence presented here should be viewed with caution. Furthermore, the included studies mainly reflect the earlier stage of the pandemic up to March 2021, and variants of concern were not well accounted for in the modelling literature at that time. This may have had implications on which group to prioritise for vaccination considering differences of transmissibility between variants. Finally, to highlight key findings across all studies, we categorised the reviewed studies according to the broad public health objectives that they aimed to fulfil. However, this categorisation may have obscured some nuances within studies, such as where there were variations in study conclusions grouped under the same category.The findings of this systematic literature review have provided empirical evidence for the prioritisation of seniors for vaccination to minimise COVID-19 deaths and young people to minimise COVID-19 transmission. However, there remain critical gaps in the evidence around strategies that reduce overall health outcomes, considering the costs of different prioritisation strategies and for low- and middle-income settings. The research gaps identified can help to guide the direction of further research on vaccination prioritisation as the pandemic continues to evolve.Additional file 1. Models of COVID-19 vaccine prioritisation: a systematic literature search and narrative review includes Tables S1 to S9. Table S1 – Search strategy. Table S2 – Conclusions of studies on optimal vaccination priority group to minimise deaths from COVID-19 with study comparators. Table S3 - Exceptions to the majority of study conclusions on optimal vaccination priority group to minimise deaths from COVID-19. Table S4 - Conclusions of studies on optimal vaccination priority group to minimise cases of COVID-19 with study comparators. Table S5 - Exceptions to the majority of study conclusions on optimal vaccination priority group to minimise cases from COVID-19. Table S6 - Characteristics of the included UMIC and LMIC studies including supply and coverage assumptions made. Table S7 - Summary of the results of the sensitivity analyses conducted by the included studies and whether this influenced the recommendation of prioritisation strategy. Table S8 - Exceptions to the majority of study conclusions on optimal vaccination priority group to minimise deaths and cases of COVID-19 organised by level of coverage by the end of the modelled vaccination campaign. Table S9 - Summary of evidence from the systematic literature review supporting the prioritisation of groups in the WHO SAGE vaccine prioritisation roadmap under different supply scenarios during community transmission.Additional file 2. Full extraction sheet for the studies included in the narrative synthesis.


The COVID-19 global pandemic has resulted in a large number of people suffering from emotional problems. However, the mechanisms by which intolerance of uncertainty (IU) affects negative emotions during the COVID-19 pandemic remain unclear. This study aimed to explore the mediating role of pandemic-focused time and the moderating role of perceived efficacy in the association between IU and negative emotions during the COVID-19 pandemic based on the uncertainty-time-efficacy-emotion model (UTEE). 1131 participants were recruited to complete measures of COVID-19 IU, pandemic-focused time, perceived efficacy, negative emotions and demographic variables during the COVID-19 pandemic. The results showed that COVID-19 IU was significantly and positively associated with negative emotions, and this link could be mediated by pandemic-focused time. Moreover, the direct effect of COVID-19 IU on negative emotions was moderated by perceived efficacy. Specifically, the direct effect of COVID-19 IU on negative emotions was much stronger for individuals with lower levels of perceived efficacy. The current study further extended the previous integrative uncertainty tolerance model. Furthermore, the study suggested that policy makers and mental health professionals should reduce the general public’s negative emotions during the pandemic through effective interventions such as adjusting COVID-19 IU, shortening pandemic-focused time and enhancing perceived efficacy. Coronavirus disease COVID-19) is an extremely severe and highly contagious respiratory disease that has erupted in over 220 countries and territories, with 119.22 million confirmed cases and more than 2.64 million deaths according to a weekly report from the World Health Organization, as of 14 March 2021 9 is an e and exacThe integrative uncertainty tolerance model  suggesteIntolerance of uncertainty (IU) refers to a dispositional incapacity to endure the negative responses caused by the perception of uncertainty due to a lack of key or sufficient information . The levPandemic-focused time reflects the behavior of seeking information, which is one type of behavioral responses of individuals to IU ,19,20. TPerceived efficacy played an important role in the self-regulation of negative emotion during uncertain situations. Faced with uncertain events, people are not always passive perceivers but can actively adjust. In pandemics, perceived efficacy refers to individuals’ confidence that performing preventive measures can effectively alleviate the pandemic and individuals’ belief in their ability to effectively cope with a health threat ,27. AccoBased on previous studies on the relationships among these variables, we propose a theoretical model to explore how COVID-19 IU influences individuals’ negative emotion during the COVID-19 pandemic see . We propThis web-based cross-sectional design research was approved by the Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences, and conducted in accordance with the Declaration of Helsinki. All participants were recruited online from 33 provinces of China from 24 February 2020 to 3 March 2020. A total of 1131 participants completed the questionnaires. Data from participants who gave an incorrect response to a question used to detect whether they answered the questionnaire carefully were excluded from the analysis. Finally, data from 1022 participants (90.4%) were entered into the final statistical analyses. Information about the descriptive characteristics of the participants is presented in COVID-19 IU was measured by three items adapted from a well-established intolerance of uncertainty scale : “The unps < 0.001, see Fear, anxiety and depression were used to represent negative emotions in the COVID-19 pandemic ,35,36. RPandemic-focused time spend on COVID-19 was measured by asking participants, “How much time do you spend focusing on COVID-19 information per day on average?” The options were as follows: (a) 10 min or less, (b) 11–30 min, (c) 31–60 min, and (d) more than 60 min.Perceived efficacy was assessed using four items from a well-established perceived efficacy scale  See Tab. These 4Participants completed the survey by scanning the QR code of the questionnaire link. After reading and signing the informed consent form, participants were required to report their demographic data and all of the questionnaires. Only one response from each IP address was allowed. This web-based survey was completely voluntary and noncommercial.Data were analyzed using SPSS Version 20.0. Descriptive statistics were used to describe the sample characteristics of each factor. Pearson correlation analyses were used to explore associations between factors conforming to the prerequisites for the following analysis. We tested the hypothesized model using the SPSS macro PROCESS (Model 5) . The biar = 0.170, p < 0.001), and negative emotions . The association between pandemic-focused time and negative emotions  and the association between perceived efficacy and negative emotions  were significant. However, the association between COVID-19 IU and perceived efficacy  as well as the association between pandemic-focused time and perceived efficacy  were not significant.The means, standard deviations, and correlation matrix of the variables were presented in The main results of the proposed model consisted of four parts: Model 1, Model 2, the indirect effect analysis and the conditional direct effect analysis see . Model 1F = 20.372, rp < 0.001) and Model 2  showed that the direct effect of COVID-19 IU on negative emotions was significant . The positive predictive effect of COVID-19 IU on pandemic-focused time  and the positive predictive effect of pandemic-focused time on negative emotions  were also significant. Moreover, the upper and lower bounds of the bootstrapped 95% CI for the indirect effect of COVID-19 IU on negative emotions through pandemic-focused time did not include 0, indicating that the mediation effect of pandemic-focused time was significant . These results suggested that pandemic-focused time played a partial mediating role in the relationship between COVID-19 IU and negative emotions.Controlling for gender, age and education background, the results of Model 1 . Furthermore, the interaction terms of COVID-19 IU and perceived efficacy showed significant effects on negative emotions . The results of the conditional direct effect analysis showed that the direct effect of COVID-19 IU on negative emotions was significant at each level of perceived efficacy as the upper and lower bounds of the bootstrapped 95% CI excluded 0. Compared to individuals with high perceived efficacy , COVID-19 IU had a stronger effect in predicting negative emotions among individuals with low perceived efficacy   see . Thus, tThe worldwide pandemic of COVID-19 has led to severe emotional problems for many people. The current study first used pandemic-focused time as a mediating variable and perceived efficacy as a moderating variable to discuss the mechanism of negative emotions during the COVID-19 pandemic. The results indicated that people who could not tolerate uncertainty had higher levels of negative emotions. COVID-19 IU increased negative emotions by increasing pandemic-focused time. The effect of COVID-19 IU on negative emotions was moderated by perceived efficacy. Specifically, for individuals with a low level of perceived efficacy, the higher their level of COVID-19 IU, the higher their levels of negative emotions were. The current research validated the role of the UTEE model in the COVID-19 pandemic. Simultaneously, this study suggested effectively decreasing COVID-19 IU, reducing pandemic-focused time and enhancing individuals’ perceived efficacy could reduce negative emotions during the COVID-19 pandemic.We found that COVID-19 IU was positively associated with negative emotions, suggesting that individuals with higher COVID IU levels were more likely to feel fear, anxiety and depression. First, when people face threats, COVID-19-related uncertainty can lead to negative emotions. The COVID-19 pandemic is a huge crisis for human society that is accompanied by extreme threats. Threat-related uncertainty could cause negative emotions, such as fear and anxiety . Second,Our findings showed that pandemic-focused time played a mediating role between COVID-19 IU and negative emotions. On the one hand, when faced with uncertainty, individuals with high IU spent more time trying to convert uncertainty into certainty than individuals with low IU during the COVID-19 pandemic. Individuals with high COVID-19 IU were more likely to lose control and less likely to tolerate uncertainty than those with low IU. The former paid too much attention to health-related information  to meet their greater informational needs than those with low IU ,50. On tPerceived efficacy moderated the direct effect of COVID-19 IU on negative emotions. Specifically, compared with individuals with high perceived efficacy, individuals with low perceived efficacy had more difficulty regulating the negative emotions caused by IU. On the one hand, individuals with a high level of perceived efficacy believed that prevention measures for the COVID-19 pandemic were effective. The efficacy of governmental actions to prevent the COVID-19 pandemic was higher for people who were satisfied with their government prevention measures than those from other countries . They maIn our research, COVID-19 IU increased negative emotions. Due to the specific characteristics of COVID-19, the high uncertainty of COVID-19 cannot be permanently resolved in the short term. COVID-19-related uncertainty could lead to negative emotions and endanger people’s mental health, especially for subpopulations who are at increased risk of being affected by the pandemic. Thus, more attention should be paid to monitoring and focusing on individuals with high COVID-19 IU to prevent them from experiencing excessive negative emotions.In this case, convenient and effective prevention strategies are urgently needed. Our research found that COVID-19 IU, pandemic-focused time and perceived efficacy can regulate the negative emotions caused by the uncertainty of the COVID-19 pandemic. Therefore, we proposed three strategies to alleviate negative emotions during the COVID-19 pandemic. The first strategy is reducing COVID-19 IU to reduce negative emotions. Several therapies can help individuals with high COVID-19 IU to relieve negative emotions by increasing acceptance of uncertainty. For example, cognitive behavioral therapy targeting IU (CBT-IU) can help individuals reappraise uncertainty and provide cognitive modification for their unrealistically positive fantasies of seeking complete certainty and exposure training to uncertainty . The secThere are several limitations in the present study. First, although the reliability and validity of the variables in our study reached an acceptable or excellent level, there is still room for improvement in the measurement of some variables. Due to the specificity of the COVID-19 pandemic, all of the measurements were completed online. It is necessary to reduce some variable questions to ensure that the subjects can complete the data carefully and that the data can be collected effectively. In the future, more representative items could be selected according to the situation to further improve the reliability and validity of the research without sacrificing the quality of the respondents’ answers. Second, our sample was limited to a general adult population. Although we excluded the interference of age, gender, and education level, it is undeniable that these variables still have implicit biases. Future studies should further consider the role of the above factors in the UTEE model, and more targeted protection should be provided for specific populations, including other age groups, patients with emotional disorders, populations closely associated with the pandemic , and populations with high levels of education and related disciplinary backgrounds . Third, this study was a cross-sectional study, and only correlation between these variables can be determined. A longitudinal design and clinical trials should be used in the future to determine the causal relationship between these variables.The current study constructed a UTEE model to elucidate the effects of individual differences in COVID-19 IU on negative emotions during the COVID-19 pandemic. The results showed a positive association between COVID-19 IU and negative emotions, which was mediated by pandemic-focused time. Moreover, the effect of COVID-19 IU on negative emotions was moderated by perceived efficacy. Accordingly, we propose three strategies to alleviate the negative emotions caused by IU during the COVID-19 pandemic, including decreasing individuals’ COVID-19 IU, reducing the time spent on the COVID-19 pandemic and enhancing perceived efficacy in relation to COVID-19.


Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19.ClinicalTrials.gov (NCT04381936).RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation  and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days . In an analysis of all randomly assigned patients (regardless of baseline antibody status), 943 (19%) of 4839 patients allocated to casirivimab and imdevimab versus 1029 (21%) of 4946 patients allocated to usual care died within 28 days . The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients . There were no deaths attributed to the treatment, or meaningful between-group differences in the pre-specified safety outcomes of cause-specific mortality, cardiac arrhythmia, thrombosis, or major bleeding events. Serious adverse reactions reported in seven (<1%) participants were believed by the local investigator to be related to treatment with casirivimab and imdevimab.In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative  at baseline but not in those who were seropositive at baseline.UK Research and Innovation  and National Institute of Health Research. Monoclonal antibodies are a set of identical antibodies that have high specificity and affinity for a single epitope. They have been shown to be safe and effective in selected viral diseases when used for prophylaxis  or treatment (Ebola virus disease).SARS-CoV-2 infection is initiated by binding of the viral transmembrane spike glycoprotein to angiotensin-converting enzyme 2 on the surface of host cells.12Evidence before this studyWe searched MEDLINE, Embase, and medRxiv from Sept 1, 2019, up to Sept 9, 2021, for randomised trials or meta-analyses of trials evaluating the effects of antiviral monoclonal antibody therapy in patients admitted to hospital with COVID-19, using the search terms  and  trial is the largest randomised trial of antiviral monoclonal antibody therapy in patients admitted to hospital with COVID-19. We found that in 3153 COVID-19 patients admitted to hospital without detectable antibodies to SARS-CoV-2 at randomisation , the monoclonal antibody cocktail of casirivimab 4 g with imdevimab 4 g reduced 28-day mortality, increased the probability of being discharged alive within 28 days, and, among patients who were not receiving invasive mechanical ventilation at randomisation, reduced the probability of progression to the composite outcome of invasive mechanical ventilation or death. The benefits were consistent in all subgroups of seronegative patients. The effect of this treatment differed significantly between patients who were seronegative or seropositive at baseline, with benefit only observed in the seronegative study population.Implications of all the available evidenceOur findings show that the combination of casirivimab 4 g and imdevimab 4 g given together as a single intravenous infusion improved survival and other clinical outcomes in patients admitted to hospital with COVID-19 who did not have detectable anti-SARS-CoV-2 antibodies . We observed no clinical benefit in patients who did have detectable anti-SARS-CoV-2 antibodies at baseline.Casirivimab and imdevimab are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, which bind specifically to the receptor binding domain of the spike glycoprotein of SARS-CoV-2, blocking viral entry into host cells.In a clinical study in adult outpatients with SARS-CoV-2 infection and risk factors for severe COVID-19, the combination of casirivimab and imdevimab was well tolerated and, compared with placebo, reduced viral load in the upper airway, shortened the time to symptom resolution, and reduced the composite outcome of COVID-19-related admission to hospital or all-cause mortality.However, to date, no virus-directed therapy has been shown to reduce mortality in patients admitted to hospital with COVID-19, for whom the only treatments so far shown to reduce mortality have been those that modify the inflammatory response.The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an investigator-initiated, individually randomised, controlled, open-label, platform trial designed to evaluate the effects of potential treatments in patients admitted to hospital with COVID-19. Details of the trial design and results for other possible treatments  have been published previously.Patients admitted to hospital were eligible for the study if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Patients who had received intravenous immunoglobulin treatment during the current admission and children weighing <40 kg or aged <12 years were not eligible for randomisation to casirivimab and imdevimab. Pregnant and breastfeeding women were eligible for inclusion. Written informed consent was obtained from all patients, or a legal representative if they were too unwell or unable to provide consent.Baseline data were collected using a web-based case report form that included information on demographic characteristics, the level of respiratory support, major comorbidities, suitability of the study treatment for a particular patient, and treatment availability at the study site . Data onBaseline presence of anti-SARS-CoV-2 antibodies was determined for each participant using serum samples taken at the time of randomisation. Analysis was done at a central laboratory using the Oxford Immunoassay , a validated 384-well plate indirect ELISA for anti-spike IgG .34 PartiEligible and consenting patients were assigned (1:1:1) to either usual standard of care, usual standard of care plus casirivimab and imdevimab (antibody combination), or usual standard of care plus convalescent plasma , using web-based simple (unstratified) randomisation with allocation concealed until after randomisation . The triAs a platform trial, and in a factorial design, patients could be simultaneously randomly assigned to other treatment groups: azithromycin, colchicine, aspirin, or baricitinib versus usual care. Further details of when these factorial assignments were open is in the NCT04426695) and outpatient (NCT04425629) studies of the safety, tolerability, and efficacy of casirivimab and imdevimab .Patients allocated to the antibody combination were to receive a single dose of casirivimab 4 g and imdevimab 4 g administered together in 250 ml 0·9% saline infused intravenously over 60 min (plus or minus 15 min) as soon as possible after randomisation. The dose of 4 g per antibody was chosen to maximise the probability of a therapeutic effect while ensuring patient safety, based on preliminary data from inpatient  or death. Pre-specified subsidiary clinical outcomes were use of invasive or non-invasive ventilation among patients not on any ventilation at randomisation, time to successful cessation of invasive mechanical ventilation , and use of renal replacement therapy . Information on suspected serious adverse reactions was collected in an expedited way to comply with regulatory requirements. Details of the methods used to ascertain and derive outcomes are in the Pre-specified safety outcomes were cause-specific mortality, major cardiac arrhythmia, and thrombotic and major bleeding events . Information on early safety outcomes at 72 h after randomisation  ceased on Feb 19, 2021, on the advice of the study's data monitoring committee and in accordance with the protocol.For all outcomes, we did intention-to-treat analyses comparing patients randomly assigned to casirivimab and imdevimab with patients who were randomly assigned to usual care but for whom the antibody combination was both available and suitable as a treatment. For the primary outcome of 28-day mortality, the log-rank observed minus expected statistic and its variance were used to both test the null hypothesis of equal survival curves  and to calculate the one-step estimate of the average mortality rate ratio (RR). We constructed Kaplan-Meier survival curves to display cumulative mortality over the 28-day period. We used the same method to analyse time to hospital discharge and successful cessation of invasive mechanical ventilation, with patients who died in hospital censored on day 29. Median time to discharge was derived from Kaplan-Meier estimates. For the pre-specified composite secondary outcome of progression to invasive mechanical ventilation or death within 28 days , and the subsidiary clinical outcomes of receipt of ventilation and use of haemodialysis or haemofiltration, the precise dates were not available and so the risk ratio was estimated instead. Estimates of rate and risk ratios are shown with 95% CI.In the light of new evidence that became available during the trial, it was hypothesised that any beneficial effect of casirivimab and imdevimab would be larger among seronegative participants (and might be negligible in seropositive participants).The full database is held by the study team, which collected the data from study sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford .ClinicalTrials.gov (NCT04381936).As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the COVID-19 pandemic. On April 27, 2021, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that, with more than 9700 patients recruited to the casirivimab and imdevimab comparison and average daily recruitment of four patients, further recruitment was unlikely to increase the reliability of the results materially and so should discontinue . The staThe funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Regeneron Pharmaceuticals supported the study through supply of casirivimab and imdevimab and DMW provided comments on the manuscript as a member of the writing committee.Between Sept 18, 2020, and May 22, 2021, 11 464 (47%) of 24 343 patients enrolled into the RECOVERY trial at one of the 127 participating sites were eligible to be randomly assigned to casirivimab and imdevimab  of 4839 patients in the casirivimab and imdevimab group and 4916 (99%) of 4946 patients in the usual care group. Among patients with a completed follow-up form, 90% assigned to casirivimab and imdevimab received casirivimab and imdevimab; no patients assigned to usual care received casirivimab and imdevimab . Use of Primary and secondary outcome data are known for more than 99% of randomly assigned patients. In patients who were known to be seronegative at baseline, allocation to casirivimab and imdevimab was associated with a significant reduction in the primary outcome of 28-day mortality compared with usual care alone: 396 (24%) of 1633 patients in the casirivimab and imdevimab group died versus 452 (30%) of 1520 patients in the usual care group , sudden hypotension (66 [4%] vs 39 [2%]), and thrombotic events (31 [2%] vs 24 [1%]) was numerically higher in the casirivimab and imdevimab group versus the usual care group, and the frequency of sudden worsening in respiratory status (369 [21%] vs 372 [22%]) and clinical haemolysis (26 [1%] vs 31 [2%]) was numerically lower . In the overall study population, the reported frequency of fever  significantly reduced 28-day mortality by about one-fifth compared with usual care, an absolute benefit of six fewer deaths per 100 patients allocated the treatment. In addition, casirivimab and imdevimab was associated with an increased rate of discharge alive from hospital within the first 28 days and a reduced rate of progression to invasive mechanical ventilation or death in these patients. By contrast, no such benefits were seen for patients who were anti-SARS-CoV-2 antibody positive at randomisation. Consequently, when all patients were considered together (including those with unknown antibody status), casirivimab and imdevimab was associated with non-significant differences in clinical outcomes. Randomised clinical trials of three neutralising monoclonal antibody preparations  in patients admitted to hospital for COVID-19 were all terminated early based on interim futility analyses.Based on our findings, any therapeutic use of casirivimab and imdevimab combination in the hospital setting would be best restricted to seronegative patients, as has now been implemented in the UK based on our results.This study was conducted predominantly at a time before the widespread use of SARS-CoV-2 vaccines, when serostatus  was reflective of acute response to infection. Now, however, seropositive status might additionally reflect the response to previous SARS-CoV-2 vaccination rather than acute infection. The vaccine-induced antibody response might be quantitatively and qualitatively different to the virus-induced antibody response. Although serological testing strategies, such as testing for antibodies against both spike and nucleocapsid proteins, might help to distinguish between vaccine-induced versus acute virus-induced antibody responses, it is not known if casirivimab and imdevimab treatment would be beneficial in vaccinated patients with COVID-19 who are S-antibody positive but N-antibody negative. The reliability of seropositive status as a predictor of therapeutic non-response to monoclonal antibodies is further complicated by the emergence of the B.1.1.529 variant (omicron) that can evade antibodies raised against earlier SARS-CoV-2 variants. Going forward, antigen status might be a more meaningful biomarker of potential therapeutic response to monoclonal antibodies than antibody status.In October, 2020, the independent data monitoring committee of an industry-sponsored trialMonoclonal antibodies are susceptible to the evolution of viral resistance if substitutions in the targeted epitope reduce or abrogate antibody binding, and a US Emergency Use Authorisation for monotherapy with the monoclonal antibody LY-CoV555 was revoked because of resistance in several major virus variants.The strengths of this trial included that it was randomised, had a large sample size, broad eligibility criteria, and more than 99% of patients were followed up for the primary outcome. The study has some limitations: information on virological outcomes was not collected, nor was information on radiological or physiological outcomes. Although this randomised trial is open label , the outcomes are unambiguous and were ascertained without bias through linkage to routine health records. The dose of casirivimab and imdevimab used in this study was high compared to those used in outpatient studies; understanding the effects of lower doses would require additional evidence from a randomised controlled trial.In summary, this large, randomised trial provides the first evidence that an antiviral therapy can reduce mortality in patients admitted to hospital with COVID-19. The results support the use of the monoclonal neutralising antibody combination of casirivimab and imdevimab in seronegative patients admitted to hospital with COVID-19 caused by SARS-CoV-2 variants that are sensitive to these antibodies.online. As described in the protocol, the trial steering committee will facilitate the use of the study data and approval will not be unreasonably withheld. Deidentified participant data will be made available to researchers registered with an appropriate institution within 3 months of publication. However, the steering committee will need to be satisfied that any proposed publication is of high quality, honours the commitments made to the study participants in the consent documentation and ethical approvals, and is compliant with relevant legal and regulatory requirements . The steering committee will have the right to review and comment on any draft manuscripts before publication. Data will be made available in line with the policy and procedures described at: https://www.ndph.ox.ac.uk/data-access. Individuals wishing to request access should complete the form at https://www.ndph.ox.ac.uk/files/about/data_access_enquiry_form_13_6_2019.docx and e-mail to: data.access@ndph.ox.ac.uk.The protocol, consent form, statistical analysis plan, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, and other relevant study materials are available DMW is an employee of Regeneron Pharmaceuticals and holds shares or share options in the company. All other authors declare no competing interests or financial relationships relevant to the submitted work. No form of payment was given to anyone to produce the manuscript. The Nuffield Department of Population Health at the University of Oxford has a staff policy of not accepting honoraria or consultancy fees directly or indirectly from industry (see https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf).


The energy sensor AMP kinase (AMPK) and the master scaffolding protein, AXIN, are two major regulators of biological processes in metazoans. AXIN-dependent regulation of AMPK activation plays a crucial role in maintaining metabolic homeostasis during glucose-deprived and energy-stressed conditions. The two proteins are also required for muscle function. While studies have refined our knowledge of various cellular events that promote the formation of AXIN-AMPK complexes and the involvement of effector proteins, more work is needed to understand precisely how the pathway is regulated in response to various forms of stress. In this review, we discuss recent data on AXIN and AMPK interaction and its role in physiological changes leading to improved muscle health and an extension of lifespan. We argue that AXIN-AMPK signaling plays an essential role in maintaining muscle function and manipulating the pathway in a tissue-specific manner could delay muscle aging. Therefore, research on understanding the factors that regulate AXIN-AMPK signaling holds the potential for developing novel therapeutics to slow down or revert the age-associated decline in muscle function, thereby extending the healthspan of animals. Studies have shown that age-associated decline in muscle function is multifactorial and affected by genetic and environmental factors. While many genes have been identified that contribute to muscle development and function, their mechanisms of action are not well understood.With aging, there is a decline in skeletal muscle mass and function. Aging muscle undergoes a shift in the balance between myogenic potential and fibrogenic activity that leads to reduced capacity of the muscle to repair and regenerate. AMPK plays a crucial role in sensing intracellular energy levels and keeping a balance between cellular metabolism and growth.This review discusses a novel signaling network involving AXIN and AMP-activated protein kinase (AMPK) in maintaining muscle health that offers a new perspective on promoting healthy aging. Both these proteins are conserved in metazoans. AXIN is an established scaffolding protein that acts to integrate inputs from multiple signaling molecules, leading to the regulation of downstream effectors.C. elegans has revealed that the AXIN family member PRY-1 is necessary for animals’ normal motility and health, and its activated form promotes longevity by maintaining muscle mitochondrial homeostasis. A similar function was previously ascribed to the AMPK catalytic subunit homolog AAK-2., The genetic and biochemical experiments revealed that PRY-1 and AAK-2 work together, likely through protein-protein interaction, and PRY-1 is required for AAK-2-mediated beneficial effect on muscle health and lifespan  complex dependent manner , promotes AMPK phosphorylation by LKB1, leading to AMPK activation. In a separate study involving myotubes and mice gastrocnemius muscle tissue, exercise stimulated both AMPK and Rac1 while increasing the cellular levels of AXIN1. Accordingly, reducing the AXIN1 function blocked GTP loading of Rac1, AMPK activation, and glucose uptake in the exercising muscles. Additionally, it was shown that muscle-specific knockout (KO) of the AXIN1-binding Ragulator subunit LAMTOR1 completely abolished treadmill exercise-stimulated AMPK activation in gastrocnemius muscle. Together, these data demonstrate the crucial role of AXIN tethering in activating AMPK, which promotes muscle metabolism and benefits linked to exercise.The Axin-containing complexes are also reported in mammalian systems. Following metformin treatment and glucose deprivation,  mice are phenotypically normal and exhibited no impairment of AMPK regulation or glucose uptake. In skeletal muscle, AMPK signaling has been linked to both acute and chronic exercise adaptations, in addition to a broad range of skeletal muscle disease states and ageing., Together these data support the growing evidence that both AXIN and AMPK and their signaling cascade are crucial to maintaining healthy muscles and slowing organismal deterioration with aging.Consistent with the role of AXIN in AMPK activation and myogenesis, AMPK is shown to be crucial for regulating skeletal muscle development, growth, and degradation., Both these treatments cause the mTORC1 components, RAPTOR and mTOR, to dissociate from the v-ATPase-Ragulator and facilitate the formation of the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex. Similarly, research inC. elegans has demonstrated that the VHA-3-LMTR-3-AXL-1/PAR-4-AAK-2 complex negatively regulates phosphorylation of the mTORC1 target S6 kinase B1 (S6K) homolog RSKS-1. As the beneficial effects of AXIN-AMPK signaling in theC. elegans study were not directly attributed to mTORC1 inhibition, the authors suggested that the signaling cascade may utilize additional factors  activity, a master regulator of anabolic pathways.ctors .  homolog. CRTC-1 is known to function downstream of AAK-2 and affects calcineurin-mediated lifespan and stress regulation inC. elegans., While AMPK and calcineurin signaling in mammalian systems regulate CRTCs in an antagonistic manner, the involvement of Axin in this regulatory network remains to be determined.–The downstream effectors of AXIN-AMPK have been reported in several other studies. Specifically, in a low glucose condition, the pathway phosphorylates proteins such as acetyl-CoA carboxylase (ACC1) and endoplasmic reticulum-localized sterol regulatory element-binding protein-1c (SREBP1c), thereby inhibiting fatty acid synthesis . Interespry-1 andaak-2 mutant transcriptomes significantly overlap with mutually up and downregulated genes. These common differentially expressed genes are associated with muscle structure development, muscle contraction, aging, and lipid metabolism. Moreover, we found that PRY-1-AAK-2 signaling functions in muscles leading to activation of AAK-2 in a cell-non-autonomous manner and phosphorylation and translocation of the FOXO transcription factor homolog DAF-16 into the intestinal cell nuclei .C. elegans, PRY-1 and AXL-1 possess the characteristic domains for the AXIN family of proteins and negatively regulate WNT signaling., It has been shown that AXL-1 functions redundantly with PRY-1 to regulate the WNT effector protein BAR-1/β-catenin during the formation of the vulva and migration of Q neuroblast. However, both AXINs are functionally not equivalent and play roles independently to control specific processes. For example, PRY-1 is necessary for lipid metabolism, healthspan, lifespan, and seam cell development, whereas AXL-1 regulates excretory cell development.,,– Recent experiments from our lab also highlight functional differences between the two Axin proteins. While PRY-1 and AXL-1 are necessary for metformin-induced lifespan extension, only PRY-1 is required for glucose deprivation mediated longevity inC. elegans . These same treatments, i.e., metformin and glucose deprivation, are known to extend the lifespan in an AAK-2-dependent manner., Overall, these studies demonstrate that AXIN homologs in every system have shared as well as unique functions. However, whether these proteins can redundantly activate AMPK remains to be investigated.In By contrast, very high AMP levels phosphorylate AMPK in a manner that does not involve AXIN1 and probably occurs via a conformational change in AMPK. Whether AXIN-dependent activation of AMPK also requires a similar change in AMPK conformation is unclear. Furthermore, it is unknown how glucose levels facilitate the complex formation and differential activation of AMPK by LKB1.Recent reports demonstrate that the lysosomal AXIN-AMPK signaling can be activated by glucose deprivation independently of AMP/ATP ratios. However, the medium-to-high elevation of AMP extends the activation of both cytosolic and lysosomal AMPK, which is also dependent on AXIN1.,, Another could be subcellular localization. While the AXIN-AMPK complex is localized to lysosomes and cytoplasm, the changes in their activities in response to external stimuli are poorly understood., Both factors are broadly expressed and in overlapping domains; however, whether their interactions are global or restricted to specific tissues remains to be determined. In this regard, it is worth mentioning that AMPK functions cell non-autonomously inC. elegans, and we have reported that the protein is needed in both muscles and intestine to mediate beneficial effects of constitutive expression of AXIN in muscles.Several other factors may also limit AXIN and AMPK mediated signaling. One of these is post-translational modification. AXIN activity is known to be regulated by phosphorylation. As mentioned above, our analysis ofC. elegans pry-1 andaak-2 transcriptomes has revealed many overlapping genes that are differentially expressed. However, more work is needed to identify and validate common targets of AXIN-AMPK signaling that are involved in maintaining muscle health in different systems. Identification of such target genes could lead to a better understanding of molecular mechanisms underlying the signaling network and the development of diagnostic markers and therapeutic interventions to promote muscle health.Given that AMPK is involved in many different processes and regulates many downstream targets, one might expect that AXIN-AMPK interaction co-regulates a subset of the targets. In support of this, a recent paper suggests that AXIN-AMPK signaling phosphorylates targets that are different from ATP/AMP-dependent AMPK signaling.We envisage several exciting research avenues involving AXIN-AMPK signaling. While substantial knowledge has been gained in terms of processes that each one participates in and mechanisms underlying their function, little is known how the interactions between the two proteins are regulated, leading to changes in the expression of target genes that carry out various roles. Below are some of the potential research directions to address the questions in the previous section.C. elegans (PRY-1 and AXL-1) and mammalian systems (AXIN1 and AXIN2) can activate AMPK,,,, the redundancies between the homologs and their tissue-specific interactions with AMPK are unknown. Moreover, the differences in lifespan and lipid metabolism phenotypes between the two AXIN mutants inC. elegans raise the question of functional equivalency regarding AMPK activation in physiological conditions. Future research along these lines should refine our understanding of AXIN-AMPK signaling and its conservation in eukaryotes.While it has been shown that the AXIN homologs in bothDepending on the context, signaling pathways may utilize different mechanisms to regulate their responses. In this regard, research in the following areas should improve our understanding of the regulatory mechanism of AXIN-AMPK signaling. First, whether a conformational change in AMPK following AXIN binding occurs similar to the AMP-dependent mechanism. Second, the role of post-translational modification of AXIN in activating AMPK. Third, identifying a specific region of the multidomain AXIN protein required for AMPK interaction that, in turn, may uncover potential competitors to modulate the signaling. And, finally, the discovery of factors affecting subcellular localizations of both AXIN and AMPK and, in turn, their interactions., Consistent with this, PRY-1/AXIN is required for MOM-2/WNT mediated lifespan regulation, and MOM-2 is expressed in the body wall muscles ofC. elegans. It remains to be explored whether AXIN function in muscles is regulated in a WNT-dependent manner in eukaryotes.Other modes of regulation of AXIN-AMPK signaling may include spatial and temporal changes in AXIN expression. AXIN is not only a negative regulator but also a downstream target of the WNT signaling.C. elegans extends the lifespan and improves muscle health in older adults. Whether forced expression of mammalian AXIN in muscles may also promote the healthspan of animals by activating AXIN-AMPK signaling requires investigation. In line with this, expression analysis of AXIN1 and AXIN2 in old adults and patients with a muscle disease should prove valuable.Research from our group has shown that overexpression of PRY-1/AXIN in– it is conceivable that AXIN and AMPK are involved in this process. More work is needed to understand the role of AXIN-AMPK signaling in exercise-mediated benefits.As mentioned above, AXIN and AMPK are crucial for muscle development and physiology. Furthermore, exercise promotes the activation of AMPK in an AXIN-dependent manner. Given that exercise promotes muscle health and delays aging,AXIN family of scaffolding proteins control a wide array of cellular processes by recruiting multiple factors and forming protein complexes. One of the interactors of AXIN is the well-known energy sensor AMPK. AMPK functions as a nexus between energy conservation and aging, and perturbations of its function lead to various age-related pathologies. AXIN-AMPK signaling promotes muscle health and delays age-associated deterioration. Future studies on the pathway, its interacting proteins, and tissue-specific effectors hold promise to uncover key candidates that may be targeted in the future to delay age-associated muscle degeneration and improve muscle health during aging.No data are associated with this article. This review/opinion article considers the roles of the two AXIN type proteins in AMPK signaling, focusing on muscle function and primarily on research done in C. elegans. The article nevertheless balances well what is known from different species, and highlights several areas for future investigation. The article is well written and the figures are useful. There are no major issues, as the discussion is balanced and inclusive of knowledge gained from various systems. It would have perhaps been useful to compare what is known about the two different AXIN proteins in a table  to highlight differences in an easily accessible resource.Is the topic of the opinion article discussed accurately in the context of the current literature?YesAre arguments sufficiently supported by evidence from the published literature?YesAre all factual statements correct and adequately supported by citations?YesAre the conclusions drawn balanced and justified on the basis of the presented arguments?YesReviewer Expertise:C. elegans, transcription, metabolism, stress response, longevity,I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The ‘Opinion article’ by Mallick and Gupta focusses on the in vivo function of AXIN-AMPK axis in muscle homeostasis and organismal health/aging. AMPK has long been known to regulate energy production in the context of change of ATP level due to stress, physical exercise etc. It has multiple functions and it is regulated by various means. The mode of its activation is different in response to differential levels of ATP depletion. Therefore figuring out the downstream effectors and biological effect in the context of differential levels of AMPK activation has been challenging.C elegans model is very interesting . Moreover, the AMPK signaling helps the crosstalk between muscle and intestine to coordinate the aging process. Therefore, focusing on this topic to write this short review article is very timely and appropriate. There are various evidences in last few years that a scaffolding protein AXIN binds to AMPK and regulates the AMPK signaling positively. These evidences come from studying multiple model organisms including mice, flies and worms. The more recent finding from this group that AXIN and AMPK interaction plays an important role in delaying the muscle aging and organism level aging inFirst the authors should avoid referring to their article actively with phrases such as  “study from our lab/group”. They may mention “recent study” instead.I suggest that they first discuss the in vivo findings on AXIN-AMKP signaling in other organisms such as mice and flies in muscle health, ATP homeostasis etc. They can have a sub-heading for this. Then they can bring a separate sub-titled section, which describes the findings using worm model focusing their recent findings. Essentially, I am suggesting that they break the section titled ‘AXIN-AMPK signaling’ in two parts as suggested above. This will allow them to discuss the key interesting hypothesis coming out from their work.One point to highlight in the future direction/question is how AXIN-AMPK signaling in muscles regulates the intestinal regulation of DAF-16. They can have a sub-title on this. Please suggest a few possibilities.Another point is to propose some research questions on how AXIN intersects between Wnt and AMPK signaling. What are the interesting questions in this direction that can be solved using the worm model? I have a few suggestions on the organization of this article.Is the topic of the opinion article discussed accurately in the context of the current literature?YesAre arguments sufficiently supported by evidence from the published literature?YesAre all factual statements correct and adequately supported by citations?YesAre the conclusions drawn balanced and justified on the basis of the presented arguments?YesReviewer Expertise:Genetics, C elegans, neural circuit development, neuronal regeneration, agingI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. The authors provide a largely balanced overview of current understanding regarding co-ordination between the energy sensor AMPK and well-defined scaffold protein AXIN1 to promote healthy aging, and succinctly outline knowledge gaps and future directions. A major question (for this protein biochemist at least) remains whether this occurs via direct interaction as the text and figures here suggest. Albeit an opinion piece, I think there is a degree of extrapolation and overstatement. For example, I could not find evidence in ref 7 to support the statement “...another C. elegans AXIN homolog AXL-1 forms a complex with AAK-2 following metformin treatment” on p3. Also AXIN2 redundancy has been demonstrated at the functional level, not structural, as stated on p6. The AXIN1/AMPK complex was reported in 2013 but has not been independently verified as far as I’m aware. It is not a stretch to say the model has caused controversy in the field – mainly created by difficulty in replicating the primary co-IP and this should be given due accord. The authors published work using C. elegans notes that a physical interaction requires further examination. I suggest the article would benefit from clearly distinguishing ‘function’ from ‘interaction’. I also recommend elaboration on the nature of the molecular interaction between AMPK and AXIN1, for which biochemical data are reported . Authors could comment on requirement for AMPK b-subunit myristoylation for formation of the axin/AMPK complex in vitro. The non-myristoylatable mutant b2-G2A failed to localise to lysosomes following glucose starvation. Likewise requirement for the AXIN1 region between residues 507-731, which is indispensable for stabilisation of the complex in vitro but is outside of conserved AXIN1/2 domains. Please expand on what is known of the major AXIN regulatory post translational modifications.Is the topic of the opinion article discussed accurately in the context of the current literature?PartlyAre arguments sufficiently supported by evidence from the published literature?PartlyAre all factual statements correct and adequately supported by citations?PartlyAre the conclusions drawn balanced and justified on the basis of the presented arguments?YesReviewer Expertise:Metabolic signaling pathways; structural biology; cell biologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.


An explanation of the phenomenon would lead to think that the SARS-CoV-2 virus had proliferated more in the gastric than in the respiratory field. The presence of papillitis in patients with COVID-19 has previously been documented in the scientific literature but has never been correlated with oral VSC values. Differential diagnosis includes: lingual irritation from savory or spicy foods, papillitis not linked to COVID-19 or mild alteration of the normal shape of the lingual mucosa in people who abuse alcohol.A 30-year-old male patient in general good health came to my observation for a lingual checkup. The patient had tested positive for SARS-CoV-2 with a molecular swab about 1 month earlier, with mild symptoms of COVID-19: fever at 37.6°c for a day, mild sore throat. No alteration of flavors and odors. Upon physical examination, he showed excellent dento-periodontal health and very good oral hygiene. At the tip and lingual margins, there were asymptomatic red pinpoint spots, which the patient had noticed appearing from the first day of COVID-19 symptoms. A diagnosis of papillitis had been made and an examination with a gas chromatograph Oral Chroma™  was performed to evaluate tongue Volatile Sulfur Compounds (VSC) values with the aim to intercept any gastric or respiratory problems. The report showed very high levels of (CH


Idiopathic retroperitoneal fibrosis is a rare fibro-inflammatory disease that can be associated with other IgG4-related diseases (IgG4-RDs). It is exceedingly uncommon to encounter this condition in a patient with Riedel’s thyroiditis (RT), another disease in the IgG4-RD family. We present the case of a 53-year-old man with a history of RT who presented for severe localized lower abdominal and suprapubic pain due to obstructive uropathy from extensive retroperitoneal fibrosis. The biopsy of the mass demonstrated fibro-inflammatory tissue, and its immunohistochemistry was notable for IgG4-positive plasma cells. This case highlights the challenge associated with the diagnosis and management of this rare manifestation of IgG4-RD. In a patient with a history of any form of IgG4-RDs, providers should be vigilant for any signs or symptoms that suggest the development of fibrosis in other organs. Retroperitoneal fibrosis is a rare fibro-inflammatory condition that can lead to the entrapment and obstruction of retroperitoneal structures including the ureters and infrarenal vessels such as the aorta and inferior vena cava . It is cRiedel’s thyroiditis (RT) is another rare, destructive fibro-inflammatory condition that is a part of the IgG4-RD spectrum and is the most common thyroid manifestation, with five of the six RT samples demonstrating IgG4-positive immunostaining in a Mayo clinic cohort from 1958 to 2008 . In anotA 53-year-old male with a history of RT previously treated with isthmectomy for compressive symptom relief presented with a one-week history of severe localized lower abdominal and suprapubic pain. He denied any fever, gastrointestinal symptoms, genitourinary symptoms, or weight loss. He was initially diagnosed with acute prostatitis and was treated with ciprofloxacin without improvement of symptoms, which prompted a second visit to the emergency room. Physical examination demonstrated a flat, soft abdomen with normal bowel sounds and no palpable masses, but with diffuse tenderness across the lower abdomen, especially in the right lower quadrant and suprapubic region. The patient underwent a non-contrast CT scan of the abdomen and pelvis with findings significant for an extensive, predominantly right-sided retroperitoneal mass encircling the aorta, inferior vena cava Figure , and proThe patient underwent right ureteral stent placement, which partially resolved hydronephrosis and restored kidney function. The CT-guided biopsy of the retroperitoneal mass revealed fibro-inflammatory tissue without specific features Figure . The immThe patient was finally diagnosed with IgG4-related systemic fibrosclerosis. Additional lab testing showed normal lactate dehydrogenase, uric acid, and IgG4 levels. He was started on high-dose prednisone at 60 mg daily. Throughout this time, he developed acute renal failure requiring additional stent placement by urology, as well as refractory pain necessitating the use of narcotics.Over the next few months, along with decrease in the size of the retroperitoneal mass on follow-up CT Figure , his anaGiven the presence of an IgG4-positive plasma cell infiltrate, retroperitoneal fibrosis, and history of RT, the diagnosis of IgG4-related retroperitoneal fibrosis in a patient with RT was made.IgG4-RD is an immune-mediated fibro-inflammatory condition capable of affecting multiple organs. Its prevalence is unknown, although the recognition of the disease continues to grow . CD4 T cIgG4-RD requires a broad differential specific to the organ system(s) involved. One of the patient groups that is at high risk of having this disease and requiring further evaluation are those with retroperitoneal fibrosis. Patients with retroperitoneal fibrosis are at a high risk of having IgG4-RD and thus necessitate further evaluation. The diagnostic evaluation of IgG4-RD includes histopathologic, clinical, serologic, and radiologic findings. IgG4 levels are elevated in the majority of patients, although a minority of patients have normal serum levels, as this patient did . Tissue Primary retroperitoneal fibrosis, whether it is truly idiopathic or associated with IgG4-RD, is treated with immunosuppressive therapy in addition to immediate relief via open surgical, percutaneous, or endoureteral urological interventions if significant obstruction is present. Corticosteroids are considered the first-line therapy . The proRetroperitoneal fibrosis is one of the most frequently encountered IgG4-RDs, and RT is the most common thyroid manifestation of these diseases, though Hashimoto’s can exhibit some of the same pathologic features. The two are rarely diagnosed in the same patient. In a patient with the diagnosis of any form of IgG4-RD, clinicians should remain vigilant for any signs or symptoms that suggest the development of fibrosis in other organs. A comprehensive diagnostic criterion is employed to diagnose IgG4-RD, and the patient detailed in this case met the criteria to diagnose the disease. Given his history, the above case likely represents a rare diagnosis of IgG4-related retroperitoneal fibrosis causing obstructive uropathy in a patient with a history of RT whose fibrosis improved with the initiation of corticosteroids.