Radionecrosis is a common and rising problem in neuro-oncology. Image interpretation and management of these patients has to be conducted in an interdisciplinary setting in order to offer the best medical care to patients with gliomas or brain metastases. In this article, we provide a state-of-the-art institutional guideline for the current morphological, functional, metabolic and evolving imaging tools to distinguish radionecrosis from tumor recurrence. We also discuss the therapeutic possibilities and give an outlook on future developments to tackle this challenging topic.Radiation necrosis represents a potentially devastating complication after radiation therapy in brain tumors. The establishment of the diagnosis and especially the differentiation from progression and pseudoprogression with its therapeutic implications requires interdisciplinary consent and monitoring. Herein, we want to provide an overview of the diagnostic modalities, therapeutic possibilities and an outlook on future developments to tackle this challenging topic. The aim of this report is to provide an overview of the current morphological, functional, metabolic and evolving imaging tools described in the literature in order to (I) identify the best criteria to distinguish radionecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments to tackle this challenging topic. Additionally, we provide the experience of a tertiary tumor center with this important issue in neuro-oncology and provide an institutional pathway dealing with this problem. Radiation necrosis (RN) is an uncommon but potentially severe and debilitating late sequela of radiation treatment (RT) of targets inside or near the CNS caused by significant co-irradiation of brain tissue. It is a frequent concern in the treatment of brain metastases, gliomas and AVMs, but is also relevant when targeting meningiomas or vestibular schwannomas. RN provides a challenge from a diagnostic and therapeutic perspective due to the difficulty of differentiating between RN and true tumor progression with conventional MRI and the potentially severe implications in case of misdiagnosis. RN usually occurs between 6 and 12 months after radiation therapy but can appear up to several years later in rare cases. As stereotactic RT is increasingly used for brain metastases and re-irradiation of recurrent gliomas gains popularity in combination with improved survival times, the incidence of RN is also highly likely to increase in the future. While the majority of cases of RN remain asymptomatic (CTCAE grade 1) and are apparent in follow-up MRI only, a significant proportion of cases can manifest with clinical symptoms (CTCAE grade ≥2). These vary depending on the lesion’s location, and include headaches, fatigue, nausea, paresis, sensory deficits, speech deficits and seizures. Incidence rates vary between reports and treatment concepts. A frequent indication for the application of intracranial radiation therapy are brain metastases of solid tumors. Local treatment options include single or multisession stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT) and surgery. For patients with a limited number of brain metastases SRS is increasingly utilized. SRS is now also considered a viable and safe treatment option for up to and sometimes exceeding 10 brain metastases , since tThe aim of this article is to provide an overview of multidisciplinary diagnostic and therapeutic methods, including the current morphological, functional, metabolic and evolving imaging tools in order to (I) identify the best criteria to distinguish radionecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments. Furthermore, we present the experience of a tertiary tumor center with this important differential diagnostic neuro-oncological issue and provide an institutional pathway, which is further contextualized and discussed with existing literature.An institutional pathway is presented that identifies the relevant diagnostic and therapeutic steps a patient undergoes when radionecrosis or tumor recurrence is suspected. These stepwise procedures are then discussed with the existing literature by describing (I) the best criteria for distinguishing radionecrosis lesions from tumor recurrence after radiation oncology treatment of malignant gliomas and cerebral metastases, (II) the therapeutic options and (III) future developments to address this challenging topic. Therefore, a non-exhaustive literature search was performed, and a selection of literature supporting the diagnostic and therapeutic approach is presented in a review.The institutional practice of a tertiary tumor center is represented in a flowchart  that incAfter brain irradiation, residual tumor and tumor recurrence may occur. Additionally, two different types of adverse therapeutic effects can occur: pseudoprogression and radiation necrosis. Differential diagnosis based on imaging between radionecrosis and pseudoprogression is very difficult in early stages, yet both adverse events require completely different therapeutic options.Radionecrosis is defined as the occurrence of necrotic brain tissue after RT, diagnosed by clinical presentation, MRI, FET-PET/CT and biopsy. Pseudoprogression is defined as a temporary increase in volume diagnosed by clinical presentation, MRI, FET-PET/CT and biopsy without evidence of vital tumors.Pseudoprogression is thought to be a combination of the therapeutic effect and a collapse of the blood–brain barrier. It occurs between two and five months after the initiation of radiation in approximately 20% of patients with concomitant chemoradiation and follows a self-limiting course. Histologically, neither tumor cells nor inflammatory processes are found . As diffRadiation necrosis usually occurs between three months and one year after radiotherapy  and affeEach of the three above-mentioned post-therapeutic conditions has different therapeutic consequences: a tumor recurrence requires, if possible, another operation or at least a treatment modification. Radiation necrosis can be treated conservatively with steroids or, if necessary due to a space-occupying aspect, surgically. A pseudoprogression is usually treated conservatively .To ensure the diagnosis, histopathological proof of active tumor cells is required. Thus, the diagnosis of relapse or pseudoprogression could be delayed. Early detection and the correct interpretation of adverse treatment effects are therefore crucial for patient survival.Apart from clinical signs and symptoms and routine MRI protocols, several techniques have been developed to aid differentiation, which include perfusion- and diffusion-weighted MRI, FDG- and FET-PET and MRI contrast-clearing analysis. In recent years, there have been several advances in MRI sequences or more specific radionuclides of PET, which have helped to more reliably differentiate the entities described .The main predictive risk factors known to play a significant role in the induction of RN are irradiated volume and radiation dose. In radiosurgery planning, the volume of brain receiving a radiation dose exceeding 12Gy (V12gy) or 10Gy (V10Gy) are established measures to estimate the risk of RN ,6,15. KoOther factors linked to an increased risk of RN are previous WBRT and re-irradiation, male sex, lesion location, tumor biology, as well as systemic and immunotherapies ,15,16,17Additionally, the use of chemotherapy has been implicated in RN induction, with some reports on the combined chemoradiation in the treatment of gliomas as well as on the use of capecitabine within 1 month of SRS ,11. The Due to the expected high rate of tumor progression or treatment effects after radiotherapy, monitoring for radionecrosis or tumor recurrence is crucial. The determination of radiological outcome requires observation periods of between 4 and 9 months . Close-mRoutine clinical MR examinations in our institution are conducted in standardized time intervals, usually every 3 months or upon new neurological symptoms. MR images are routinely acquired using a 1.5 or 3 Tesla MRI with a standard multichannel head coil and include the sequences described in Unfortunately, in structural MRI, including T2-weighted images, native and post-contrast T1-weighted images, progression, pseudoprogression and radiation necrosis may have a similar presentation: collapse of the blood–brain barrier with marginal contrast and hyperintensive perifocal edema in T2-weighted sequences . A tumorThe classical appearance of radionecrosis is a mass which enhances with a central necrotic area. Contrast enhancement reflects a disturbance of the blood–brain barrier secondary to the endothelial irradiation-induced damage. As the lesions tend to occur at the site of the maximum irradiation dose, they are generally expected in the immediate vicinity of the tumor site and around the excision cavity. Affected sites are predominantly in the white matter. White matter is particularly vulnerable to the secondary ischemic consequences of post-irradiation vasculopathy, resulting in perivascular coagulative necrosis, as the deep white matter has a relatively poor blood supply from the cortical arteries and is located in the watershed area of the arterial blood supply that is susceptible to ischemic damage. Consequently, the white matter arcuate fibers which also receive cortical arterial supply are more resistant to radionecrosis and are therefore usually affected later in the disease process .The morphological appearances of contrast enhancement described for gliomas after radiotherapy, including irregular, annular or nodular uptake are non-specific and contradictory ,31.Contrast uptake in radionecrosis may be nodular, linear or curvilinear . HeterogImportantly, while these effects are predominantly expected in the initial target site, single or even multifocal post-irradiation contrast enhancement can also be present distant to the initial tumor. This has been described several centimeters away, in the corpus callosum, the contralateral hemisphere, the subependymal regions and the posterior fossa , which mHypointensities suggestive of hemorrhagic changes are often observed on T2-weighted echo gradient images. These were reported in 53% of cases of radionecrosis using the conventional T2* sequence  and in 8The relevance of the space-occupying effect is typically negligible considering the size of the lesion. Yet, accompanying reactive vasogenic edema can be extensive and cause a significant space-occupying effect. In cases of possible radionecrosis, some lesions progressively enlarge with a transient increase of cytotoxic edema over a few months. However, some lesions remain stable before regressing and others regress from the beginning . TherefoOverall, in many cases, the diagnosis remains unclear with structural MRI. The morphological features of radionecrosis lesions are very similar to those of a recurrent tumor, including the type of contrast enhancement, site (both in the tumor site and remote) and possible transient deterioration . MRI changes are observed on MRI from 6 weeks after radiotherapy up to 15 months . A transWhile this transient increase in volume post-radiation is modest, an increase of more than 65% compared to the pre-therapeutic volume suggests a recurrence or continued tumor activity  . A qualitative method to distinguish both appearances is the correlation between the boundaries of the lesion seen on enhanced T1-weighted and T2-weighted imaging . CorrelaAdditionally, the amount of edema present on T2-weighted imaging by calculating the ratio between T2-weighted hyperintensity volume/T1-weighed volume after enhancement, can also be considered. When over 10, this approach reaches a positive predictive value of 92% for radionecrosis . Diffusion-weighted MRI (DWI) can represent the movement of free water  and thusThe method is nevertheless not very well suited for differentiation, since surrounding edema leads to impairments . Moreove−3 mm2/s mean compared to 2.3 × 10−3 mm2/s for radionecrosis) [−3 mm2/s) than in the radionecrosis group of patients (1.12 × 10−3 mm2/s) [The ADC ratio  has been reported to be more discriminatory than absolute ADC values with a significantly higher rADC in radionecrosis (rADC = 1.82) compared to tumor recurrence rADC = 1.43) [ [43]. Yeecrosis) . In cont3 mm2/s) ,49. One solution might be to consider ADC values in the T2-weighted hyperintense area without contrast enhancement, referred to as perilesional edema. The mean ADC in radionecrosis is not significantly different between the enhancing area and the neighboring area, while in recurrences of an infiltrative tumor the ADC is higher outside of the contrast enhancement ,44. With perfusion-weighted MRI (PWI), local tissue perfusion can be measured and compared with healthy areas. By measuring dynamic contrast agent accumulation, the relative cerebral blood volume (rCBV) can be determined. In tumor relapses, increased rCBV can be found due to increased metabolic activity and neoangiogenesis . RadiatiThe tumor capillaries of cerebral metastases resemble the ultrastructure of the original tumor more than the cerebral tissue capillaries. Increased tortuosity, lack of maturity, increased permeability and a lack of blood–brain barrier are indicators for alternate image interpretation using macromolecular contrast agents based on relative cerebral blood volume (rCBV), the relative amplitude of the peak (rHP) and the percentage signal recovery (PSR) ,53,54. AThis large overlap of CBV values renders image interpretation challenging. This effect may be explained by tumor heterogeneity, the similarity between microvascular density from metastatic recurrences and hyperplastic dilated blood vessels in post-radiation changes, the co-existence of radionecrosis lesions with tumor recurrence (50% radionecrotic tissue has been found in tissue samples from metastatic recurrence), magnetic susceptibility artifacts due to petechial hemorrhage caused by the irradiation  and melanin as an artifact impeding the analysis of the CBV .Hydrogen 1 (1H) magnetic resonance (MR) spectroscopy (MRS) enables non-invasive in vivo quantification of metabolite concentrations in the brain. The structural brain tissue degradation induced by radiotherapy is caused by early alterations in metabolic activity . These cMetabolites affected by ongoing changes include the neuronal marker N-acetylaspartate (NAA), the concentrations of which decrease as a consequence of cell death by apoptosis or neuronal dysfunction. Secondly, alterations in the biosynthesis of cell membranes and metabolic turnover are reflected by an increase in choline (Cho). Contrarily, the marker of energy metabolism Creatinine (Cr), is supposed to be unaffected by radiation damage in some literature . ConsequWhile in cases of tumor recurrence a fall in NAA can also be observed, MRS depicts a dominant rise in the Cho peak due to proliferation. The most widely calculated ratios in clinical routines for gliomas are Cho/Cr and Cho/NAA ,57. AddiSpectroscopic analysis is a promising method; however, it bears several limitations, such as lesions located close to bones due to magnetic susceptibility artifacts . AdditioImaging evaluations of treatment responses are especially challenging after the administration of Bevacizumab and similar systemic therapies, as there might be an influence of common systemic treatments on the accuracy and readability of contrast clearance and perfusion MR images. Bevacizumab (trade name Avastin), is an inhibitor of the vascular endothelial growth factor (VEGF), aimed at inhibiting neoangiogenesis. VEGF is produced by the tumor and not only promotes neoangiogenesis but also reduces the effectiveness of gap junctions and creates fenestrations in the endothelium of existing brain capillaries, leading to edema and enhancement. The amount of VEGF produced has been shown to correlate with tumor grade. Unlike the USA and Japan, Bevacizumab is not approved for first- or second-line treatment of GBM in the European Union. Nevertheless, it is most frequently used as a second line treatment in Europe, due to a lack of other agents and good clinical response in terms of symptomatic relief. In our neuro-oncological practice, Bevacizumab is used after tumor board approval for second-line treatment of patients with recurrent GBM after re-resection and re-irradiation (as appropriate). Bevacizumab is known to change imaging patterns and contrast medium uptake dynamics. It is likely to introduce a so-called pseudoresponse, which refers to the phenomenon of tumors appearing to respond to a specific treatment on imaging criteria, even though the lesion actually remains stable or has even progressed.In brain tumors imaging follow-up, especially in high grade gliomas such as glioblastoma, a rapid decrease in contrast enhancement and edema can be observed in a short period of time after the administration of antiangiogenic agents , often without any significative change in actual tumor size  or diffusion/perfusion studies ,64,65.The changes seen in pseudoresponse, which can be observed as a rapid reduction in enhancement and vasogenic edema in imaging, are largely mediated by changes in blood–brain barrier permeability rather than antiangiogenic effects, meaning that relying on enhancement and T2 signal change can be misleading when interpreting follow up MRI studies. MR spectroscopy, MR perfusion  and diffusion-weighted imaging (DWI) are particularly important in assessing the presence of residual, but now non-enhancing, tumors. Despite the fact that these advanced MRI sequences have helped in differentiating pseudoresponses from a true response, imaging follow-up is still required . EssentiThe influence of targeted or immune checkpoint therapies on image interpretation has not been investigated yet. However, to date there is no known impact of those substances on GBM. The results of imaging studies in targeted or immune-checkpoint modulating treatments may allow for future guidelines on how to interpret imaging results.Recent developments have provided radiologists with advanced MR techniques, which are currently being extensively investigated and have recently been shown to be useful in the imaging of neuro-oncology patients. Although still investigational techniques, they have been shown to have potential routine clinical application and should therefore be incorporated in decision making in the future.Despite all of their limitations, all of these above-mentioned sequences are part of standard MRI protocols.Brain metastases and radiation effects after SRS have been shown to bear a characteristic and statistically significantly different signal intensity (SI) time course, as assessed by manual regions of interests (ROI) drawing on sequential gadolinium enhancement MRI including MR studies at 2 (TP1), 15 (TP2) and 55 (TP3) min after administering the contrast agent . To perform delayed contrast extravasation MRI, an additional short MRI scan is added >1 h after a standard contrast enhanced MRI scan. For the analysis subtraction, maps are obtained in which T1-MR images acquired 5 min postcontrast are subtracted from T1-MR images acquired 80 min postcontrast. T1-MRI of the second time point are therefore registered to the location of the first time point. Finally, subtraction maps are calculated by voxel-by-voxel subtraction of the early images from the late images. The derived maps depict the spatial distribution of the contrast accumulation/clearance. Exemplarily, in the case of healthy blood vessels, as an effect of the contrast clearance from the blood, the signal decreases with time, and hence the subtraction maps between these two images show negative values (arbitrarily color-coded as blue in the maps). In contrast, in case of contrast accumulation, the maps show positive values (red) . This isIn addition to delayed contrast extravasation MRI, quantitative sequences and arterial spin labelling (ASL) sequences are tools for the quantification of image data in radiology and thus pave the way for a more objective and reproducible non-invasive diagnosis ,68,69,70Upcoming technologies might influence future approaches on MR imaging protocols for patients affected with primary brain tumors. DSC perfusion is used in standard brain tumor MR protocols at most tumor centers. Due to the added invasiveness of contrast application, associated socio-economic costs and increasing awareness of potential Gadolinium accumulation, DSC perfusion might potentially be replaced by arterial spin labelling MR perfusion, which might have potential as a diagnostic aid in the differential diagnosis of tumor recurrence, radionecrosis and pseudoprogression. Furthermore, T1-, T2- and T2*/QSM-mapping and arterial spin labelling sequences are a tool for the quantification of image data in radiology and thus pave the way for a more objective and reproducible non-invasive diagnosis ,69,70,72By means of phosphorous-based MRS (31P-MRS), various phosphorus-containing metabolites can be measured in vivo: energy-related metabolites (the energy metabolites inorganic phosphate (Pi), phosphocreatine (PCr) and adenosine triphosphate (ATP)) and cell membrane-related phospholipids (the mobile membrane phospholipid precursors phosphomonoesters (PME) and their breakdown products and intracellular signaling molecules phosphodiesters (PDE), which are related to membrane turnover) .Differences in energy and membrane metabolism have been detected with 31P-MRS between contrast-enhancing (CE) tumors and the contralateral hemisphere, normal-appearing areas of the brain, as well as brain tissue from healthy controls and further during therapy ,80,81,82Consequently, 31P-MRS can potentially be applied for differentiation between radionecrosis and tumor recurrence, yet, this warrants further investigations. However, the application of 31P-MRS is complicated by the fact that 31P-metabolism varies throughout the brain, with age and between sexes, which poses important practical implications for the application and interpretation of 31P-MRS especially in such complex metabolic changes as are introduced by radiation .Furthermore, an alternative approach might be the development of deep evolution learning for monitoring and analyzing the treatment effects of radiotherapy. In that context, the performance of clinical routine and advanced MR sequences could be included for diagnostic and prognostic examinations. The term deep evolution learning is used for finding data-driven models based on deep neural networks (NNs) to understand and analyze the evolution of images. Multi-channel data collected via different measurements, which are obtained with routine and advanced sequences in MRI, could potentially extract key figures to provide a learned model for the dynamic evolution of the disease under the external influence of radiotherapy. By enabling a more precise and objective diagnosis, deep evolution models offer the opportunity to individualize treatment planning and to guide therapy. The identification of sensitive parameters and key features that drive the temporal evolution limits the risks and could potentially serve as a warning system to assist the physician. The methodological aspects of such a biomarker, in order to be implemented as a potential outcome measure in research and clinical routine, i.e., sequence selection, needs to be investigated. By implementing a local image analyses pipeline, with growing well-defined data gained in a clinic every day, we expect tertiary centers to thereby not only achieve a robust and easily feasible diagnostic and prognostic marker with a therapeutic value but also enforce a well-structured team, including medical doctors, computer scientist and statisticians, in order to efficiently perform image analysis in both clinical routines and scientific advancement. This approach may even spare patients from the invasiveness of brain biopsy.While FET is used in our clinic as a main tracer in neuro-oncology, other tracers exist. 2-Fluor-2-desoxy-D-glucose (FDG) represents the most common agent to display increased metabolism; unfortunately, its role within the brain is limited due to the high baseline metabolism. Amino acid-based tracers have the advantage of a superior differential between tumors and normal brains .11C-methionine (11C-MET), O-2-18F-fluoroethyl-L-tyrosine (18F-FET), and 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (18F-FDOPA) are common amino acid-based tracers that have been reported in glioma  fluoroethyl-l-tyrosine (18F FET)-PET can be used to detect an existing GBM with great reliability. An important limitation in the application of the method in the course of therapy is the passive influx of the radiopharmaceutical due to a blood–brain barrier disorder in the lesion [18F-FET-PET can be employed for diagnosis [[e lesion . In caseiagnosis ,91,92,9318F-Fluoroethyl-L-Tyrosine (18F-FET) is used. 18F-FET, a radioactive Fluorine labelled tyrosine analog, is transported into cells by amino acid transporters, which are overexpressed on the tumor cell surface. Fluorine (18F) decays with a half-life of 110 min, enabling scintigraphic imaging. 18F-FET is indicated in patients with known or suspected glioma for the characterization of tumors, the monitoring of treatment and the detection of viable tumors after treatment. In accordance with guidelines, patients are injected with an activity ranging from 180 to 250 MBq via an intravenous line. The effective dose is 16µSv/MBq, resulting in an effective dose of 2.9–4.0 mSv for the administered activity. The first image is acquired 10 min after the tracer injection, followed by images at time points 20 min, 30 min, 40 min and 50 min post-injection for dynamic PET analysis. For attenuation correction a low-dose CT  of the brain is acquired. Images are reconstructed iteratively with an ordered subset maximization algorithm (OSEM). For image analysis a visual interpretation is performed: a high tracer uptake in a nodular lesion being suggestive of tumors; a low tracer uptake in a rim-like pattern being suggestive of post-treatment changes. In addition, a semi-quantitative evaluation of the lesions is applied by measuring the intensity of the tracer uptake of normal brain tissue and a lesion-to-background ratio. Time-activity curves are also generated using SUVmax values of the lesions at the predefined five different time points of image acquisition. The time to peak is defined and time-activity curves will be assigned to one of three curve patterns: (1) constantly increasing tracer uptake, (2) tracer uptake peaking between 20 and 40 min post-injection followed by a plateau and (3) tracer uptake with an early peak (<20 min post-injection) followed by a constant decrease. Curve pattern 2 and 3 are suggestive of tumors, whereas curve pattern 1 is more likely to be present in inflammatory lesions such as post-therapeutic changes.For PET-imaging, O-2-An example of the multimodal diagnosis of radiation and tumor progression is shown in A mild to moderate increase in size after radiation therapy may be observed in about 30% of all patients between a few weeks and up to 15 months after intervention . As manyThe role of hypoxia-induced factor 1 α (HIF-1 α) in the initial step of the development of radiation necrosis results in an overproduction of VEGF. Subsequent cerebral edema is caused by fragile angiogenesis. Bevacizumab as a potent anti-VEGF monoclonal antibody has been introduced in 2007 by Gonzales et al. with satisfactory responses  and showSurgical treatment is usually necessary to either ensure a histological diagnosis, to address a space-occupying effect or to resect tumor tissue if oncologically indicated. If radiation necrosis seems plausible according to the above-mentioned imaging modalities, surgery is rarely indicated. The differentiation between real tumor progression and pseudoprogression, however, poses a significant challenge and has important therapeutic implications. If the diagnosis cannot be established by radiological means only and/or uncertainty is too high, a histological verification is often required. Surgical removal can be performed in easily accessible lesions and is indicated especially in symptomatic lesions with elevated intracranial pressure . The neuGiven the data and understanding of the underlying histological processes of tumor recurrence, pseudoprogression and radiation necrosis, in which changes in vascular density and consequent contrast media washout appear to play an important role, routinely applicable imaging modalities as well as new technologies appear promising in differentiating the three entities. Thus, it could be possible to optimize the management of patients with brain tumors and metastases by means of greater diagnostic reliability and to speed up necessary treatment modifications, to improve surveillance and to detect changes of brain lesions with MRI more rapidly, to promptly offer efficacious treatment strategies. It may be possible to reduce the necessity for invasive diagnostic procedures and reduce the rate of misdiagnosis of treatment effects after radiation therapy. More efficacious therapies and consequently longer average survival times have led to higher rates of the possible treatment responses described. This trend will most likely continue in the future. In anticipation of new MR techniques potentially limiting the necessity of invasive procedures such as biopsies, a close multidisciplinary interaction and cooperation between the teams of Neurology, Neuroradiology, Neurosurgery, Nuclear medicine and Radiooncology is crucial. Readings of MRI and PET demonstrating signs of radionecrosis or tumor progress should be carefully reviewed by all involved physicians in the context of the overall clinical scenario. A multidisciplinary approach is vital not only during tumor board sessions but also in daily clinical practice in order to offer the best medical care to patients with gliomas or brain metastases suffering from radiotherapeutic side effects.


COVID-19 disproportionally affects older adults living in nursing homes. The purpose of this review was to explore and map the scientific literature on the health impact of COVID-19 and related restrictive measures during the first and second wave among nursing home residents. A specific focus was placed on health data collected among nursing home residents themselves.In this study, best practices for scoping reviews were followed. Five databases were systematically searched for peer-reviewed empirical studies published up until December 2020 in which data were collected among nursing home residents. Articles were categorized according to the type of health impact  and study focus (impact of COVID-19 virus or related restrictive measures). Findings were presented using a narrative style.Of 60 included studies, 57 examined the physical impact of COVID-19. All of these focused on the direct impact of the COVID-19 virus. These studies often used an observational design and quantitative data collection methods, such as swab testing or reviewing health records. Only three studies examined the psychological impact of COVID-19 of which one study focused on the impact of COVID-19-related restrictive measures. Findings were contradictory; both decreased and improved psychological wellbeing was found during the pandemic compared with before. No studies were found that examined the impact on social wellbeing and one study examined other health-related outcomes, including preference changes of nursing home residents in Advanced Care planning following the pandemic.Studies into the impact of the first and second wave of the COVID-19 pandemic among nursing home residents predominantly focused on the physical impact. Future studies into the psychological and social impact that collect data among residents themselves will provide more insight into their perspectives, such as lived experiences, wishes, needs and possibilities during later phases of the pandemic. These insights can inform policy makers and healthcare professionals in providing person-centered care during the remaining COVID-19 pandemic and in future crisis periods. The new coronavirus - also known as Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 (coronavirus disease 2019) - disproportionally affects older adults . Also, rLiving in a nursing home has also been found as an additional risk factor for infection and mortality due to a COVID-19 infection compared to living independently at home , 5. A nuAs a first response, nursing homes in many countries implemented restrictive measures during the first months of the COVID-19 pandemic in order to prevent an outbreak, such as strict no-visitor policies and placing infected residents into quarantine. Various studies show that such measures had a substantial impact on the health of residents, such as increased feelings of loneliness, psychological stress, apathy and depressive symptoms and may have outweighed the potential benefits of preventing further infections . In a coAfter a period of complete lockdown minor adjustments were made to these restrictions, such as allowing one visitor per resident per day. In-depth monitoring of nursing homes in the Netherlands in the first weeks after reopening the doors showed that allowing visitors again and restoring personal contact had a positive effect on the well-being of residents , 15. By Since the outbreak of the pandemic, numerous studies have examined the impact of COVID-19 and related restrictive measures on health. In line with the biopsychosocial model, which states that illness and health are the result of an interaction between biological, psychological, and social factors , these sA scoping review was conducted in order to explore and map the scientific literature on the impact of COVID-19 and related restrictive measures on nursing home residents. As many countries have seen a two-wave pattern in reported cases of COVID-19 during 2020, with a first wave during spring followed by a current second wave in late summer and autumn, we focused on studies published during the first and second waves of the pandemic (up until December 2020) [The methodological steps outlined in the framework of Arksey and O’Malley for conducting scoping reviews were followed to undertake this review . This frThe following research questions were identified:What types of health impact of the first and second wave of COVID-19 and related restrictive measures on nursing home residents have been studied?Which knowledge gaps can be identified regarding the impact of COVID-19 and related measures on the health of nursing home residents?Five scientific databases were systematically searched including PsychInfo, PubMed, CINAHL, Science Direct and Google Scholar using a search string of three categories of key words related to ‘COVID-19’, ‘nursing home’, and ‘older adults’ Appendix . The datStudies that examined the impact of COVID-19 on nursing home residents. If mixed target groups were included or compared , we only focused on study findings related to nursing home residents;Studies that examined the health impact of COVID-19 on nursing home residents, including physical, psychological and social health;Studies that examined either a direct  or indirect (e.g. impact of COVID-9 related measures of restrictions) impact of COVID-19;Data were collected among residents themselves , observations, questionnaires, interviews);Original empirical, peer-reviewed studies;Qualitative, quantitative and mixed methods studies.We excluded studies that collected data among proxies  in order to ensure we captured the health impact from the perspectives of nursing home residents themselves. Also, we excluded studies that focused exclusively on community-dwelling older adults or were not written in English.Selected articles from the different databases were imported into Endnote. After duplicates were removed, one of the authors  screened all unique titles and abstracts. In any case of doubt, the other authors were consulted to reach consensus. Next, the remaining full text articles were screened by one of the authors  for inclusion following a comparable approach. During the screening process, several joint meetings took place to ensure that all reviewers used the screening criteria in the same way.A data-extraction sheet was developed and for each included article, one of the authors  extracted the following data: publication year and month, country, study design, period of data collection or duration of the study, method of data collection, sample size of included nursing homes and residents, and basic demographics of residents (gender and age). Articles were categorized according to the type of impact of COVID-19 the study focused on. Following the biopsychosocial model of health , studiesFindings are presented using a narrative style. A descriptive summary of basic study characteristics  is provided and presented using visual representation including a table and bar chart. Results from studies solely focusing on the physical impact of COVID-19 are not reported, as this was not the primary aim of this review and was recently reported by others . In orden = 53).Figure N = 29, 48%) and the USA . Only six studies were performed elsewhere, namely in Canada [Table n Canada , 22–25 an Canada . The numn Canada –42 to 12n Canada . The numn Canada  to 696,3n Canada . Data con = 59, 98%), such as cross-sectional , retrospective  or prospective  studies. Also, 7 case series were included [Most studies used an observational study design to examine the impact of COVID-19 on nursing home residents  and mortality . Other outcomes were symptoms  and hospitalization . Less frequently, studies focused on cycle threshold values (i.e. an estimate of how much virus was likely in the sample of a PCR test) (N = 2) [N = 1) [N = 2) [n = 32, 56%) or electronic health records .Of the 60 included studies, 57 (95%) focused on the physical impact of COVID-19 on nursing home residents. All of these focused on the direct health impact of the COVID-19 virus. The most common outcomes were infection ( (N = 2) , 69, the [N = 1)  or tempe [N = 2) , 76. One [N = 2) . Data wan = 52, 91%); over half of the studies used swab testing , followed by a third of the studies that extracted physical data from electronic health records . Other quantitative data collection methods included (linked) databases , serological blood testing  [n = 2, 4%) [n = 5, 9%); four studies used interviews with residents [A variety of data collection methods were used in these studies. Most studies used quantitative methods  , 57, 63 = 2, 4%) , 73. Onlesidents , 70, 73 esidents . Other qesidents , a COVIDesidents .n = 26, 46%) or a cross-sectional study design . For example, Rutten et al. performed a large (N = 4007) prospective cohort study among Dutch nursing home residents with clinically suspected COVID-19 who where tested with a reverse transcription-polymerase chain reaction swab test in order to describe the symptomology, mortality and risk factors for mortality [Most studies that examined the physical impact of COVID-19 on nursing home residents used an observational study design, such as a prospective or retrospective cohort study designs  [Several other studies used a case series design in which a COVID-19 outbreak in a particular nursing home was described  , 59, 73. 7, 12%) . In thisThe only experimental study that was included was a non-randomised controlled study that examined the effectiveness of a coordinated, on-site medicalization programme in four Spanish nursing homes with the objective to improve survival, offering humanistic palliative care to residents in their natural environment, and reduce hospital referrals .Three studies (5%) that met our inclusion criteria focused on the psychological impact of COVID-19 on nursing home residents , 27, 53.N = 58) regarding the impact of COVID-19-related measures  on their psychological wellbeing. McArthur et al. [N = 765), between January 2017 and June 2020. The assessment tool was administered by trained registered nurses through interaction with residents. Findings of both studies were contradictory; whereas El Haj et al. found higher depression and anxiety among residents during than before COVID-19, McArthur et al. found no change in the number of residents that experienced a delirium or behavioral problems and a decrease in the proportion of residents with indications of depression during than before lockdown. A third article by Ward et al. [El Haj et al.  performer et al.  conducted et al.  describeNo studies have been published on the social impact of the first and second wave of COVID-19 and related restrictive measures on nursing home residents that collected among residents themselves.One study was included that examined the impact of COVID-19 among nursing home residents, other than the physical, psychological or social health impact. This retrospective chart review examined the impact of the COVID-19 pandemic on goals of care within Advanced Care Planning . Based oThis review aimed to scope the scientific literature published on the health impact of COVID-19 and related restrictive measures during the first and second wave of the pandemic among nursing home residents. To focus on the perspectives of residents - which provides insights into their lived experiences, wishes and needs during the COVID-19 pandemic - studies were only included if data were collected among nursing home residents. This included both objective data  as well as subjective data (e.g. data based on questionnaires). It was found that the direct impact of the COVID-19 virus on physical health among nursing home residents was studied extensively. In particular, a large number of studies - predominantly from Europe and the USA - examined the impact of COVID-19 on infection and mortality rates, symptoms and hospitalization. These numbers have been previously collated and show that the number of COVID-19-related deaths in care homes ranged from 18.6% in England and Wales (April/May 2020) to 78.2% in Canada (August/September 2020) out of deaths in total [From the perspectives of nursing home residents themselves, we identified a major knowledge gap with regard to the psychological and social impact of the first and second wave of COVID-19 and related restrictive measures. Only three included articles published in that period studied the psychological impact using data collected from nursing home residents. These studies varied in sample size, study design, data collection methods and study focus, i.e. one study focused on the psychological health impact related to a COVID-19 infection and two studies focused on the impact of COVID-19-related restrictive measures. The findings were contradictory. At the one hand, residents with dementia reported higher depression and anxiety during than before the COVID-19 crisis  and an aWhereas physical health outcomes can be studied using relatively straightforward procedures, studying social and psychological aspects of health among people with cognitive impairment can be much more challenging. Since we only included studies that collected data among nursing residents themselves, this may explain why we identified these knowledge gaps.This scoping review is the first that provides insight into empirical studies on the overall health impact of COVID-19 and related restrictive measures among nursing home residents published during the first and second wave of the pandemic in 2020. A broad search strategy was used to include studies examining both the physical impact as well as the psychological and social impact. However, several limitations of this review have to be mentioned.First, we searched for literature published in a relatively short timeframe - between the beginning of the pandemic up until December 2020. It may be possible that we have missed studies that examined the impact of the first and second wave because of a delay between acceptance and actual publication dates. Also, because we focused on studies that collected data among residents themselves, which often involves time-consuming ethical approval procedures, such studies may not yet have taken place or were not yet published within this timeframe. This may also explain why the publication date of the included studies drops off as 2020 progresses. Future updates of this review will most likely include more relevant studies that were published after December 2020 and will provide further insight into the impact of later phases of the COVID-19 pandemic on residents’ health.Second, we only included empirical and peer-reviewed studies to ensure a high-quality standard. Because grey literature was not included, we may have missed relevant reports, papers or other non-academic material published. For example, we excluded a commentary of Mo & Shi from China providing an overview of existing literature on the psychological consequences caused by COVID-19 among residents of nursing homes . To mainThird, we aimed to perform a rapid literature search given the fast developments regarding the COVID-19 pandemic. As such, the search was not performed by a librarian and only search terms were used, i.e. no MeSH/indexed terms. Also, for similar pragmatic reasons, screening and data extraction was performed by only one of the authors, which may be considered as a limitation as independency cannot be guaranteed. However, any doubts regarding inclusion of articles and data extraction were discussed jointly with other authors. Nevertheless, we recommend that future iterations of this review should include more thorough search strategies and ideally involve two authors in the screening and data extraction procedures.Lastly, the majority of included studies collected data during the first months of the pandemic – March to May 2020. Therefore, the results specifically relate to the impact of the first wave of the COVID-19 pandemic in which whole societies were in lockdown and nursing homes had to deal with frequent outbreaks, shortage in equipment, limited knowledge about consequences and treatment, and strict restrictive measures. It is likely that studies published in later phases of the pandemic provide additional  findings on the health impact among nursing home residents. Future updates of this scoping review are therefore recommended in order to include new studies and to compare the current findings to the health impact of later phases of the COVID-19 pandemic, in which related restrictive measures were eased and to the long-term health impact of COVID-19 and related measures on nursing home residents.We found that studies into the perspectives of nursing home residents regarding the psychological and social impact of COVID-19 are scarce. Data collection among nursing home residents with a form of cognitive impairment or dementia – which make up for the majority of nursing home residents – can provide important insights into their lived experiences, wishes, needs and possibilities. This aligns with the current paradigm shift in nursing home care, in which care is shifting from a biomedical care model towards a person-centered care model , 82. PerBy focusing exclusively on data collected among residents, however, we may have missed important studies that used a proxy to collect data. During the screening process, we indeed excluded a few studies that collected data on the impact of COVID-19 on the psychological and/or social wellbeing of nursing home residents among proxies. For example, Leontjevas et al. examined the impact of COVID-19 on challenging behaviors and psychological wellbeing of Dutch nursing home residents . Data weBecause this scoping review focused on literature published during the first and second wave of the COVID-19 pandemic in 2020, we also recommend future research that shed light on the overall long-term impact of the pandemic, as well as on the impact of easing restrictions. For example, Koopmans et al., studied the impact of reopening the doors of Dutch nursing homes during the COVID-19 crisis and allowing visitors again after a 2-month lockdown period. An online survey, regarding changes in resident wellbeing that were observed after the lockdown, was completed by nurses, psychologists and physicians of 26 nursing homes. Although overall visitors and staff noticed that residents seemed to enjoy the visits, became overall more active and returned to their units in good spirit after a visit, some residents experienced sadness because physical contact was prohibited. In some residents with dementia, visits seemed to result in confusion, sadness or restlessness. Consequently, staff advised against visiting these residents anymore under the circumstances of that time .Studies on the impact of COVID-19 and related restrictive measures, such as visitor restrictions and social distancing, among nursing home residents published in the first and second wave of the pandemic in 2020 focused predominantly on the physical health impact of the virus, including infection and mortality rates. Consequently, a knowledge gap exists regarding the psychological and social health impact, in particular from the perspectives of nursing home residents themselves. Therefore, we recommend further empirical studies into the impact of later phases of the COVID-19 pandemic and the long-term impact on social and psychological wellbeing of nursing home residents, with a specific focus on their own perspectives. Giving nursing home residents a voice contributes to improving person-centered care and support that is tailored to their needs and preferences during the remaining COVID-19 pandemic and in future crises .


There is hardly any report of reinfection due to coronavirus disease 2019 (COVID-19) in medical professionals from Nepal. We report a case of a 32-year-old doctor with COVID-19 reinfection. Symptoms during the first infection were mild. After one month, he was reinfected and developed diarrhea as well as a continuous high fever. His d-dimer and ferritin were much increased. Computed tomography chest showed bilateral lymph nodes, minimal pleural effusion, and scattered linear fibrosis. After discharge, his depression and myalgia persisted for one month. During reinfection, his symptoms were more severe and cost of treatment was almost eight times his monthly salary and he could not work for six weeks. Possible reasons for severe reinfection and differential diagnoses like cytokine storm, multisystem inflammatory syndrome, reactivation of COVID-19, and infection due to new variants were discussed. Whether infected or vaccinated or not, all should take recommended vaccination and primary-preventive as well as health-promotive measures. We report here a re-infection case in a young doctor.Many respiratory tract infections in human beings are often caused by four types of endemic corona viruses and reinfection with them occur eventually.2. Reverse transcription-polymerase chain reaction (RT-PCR) for COVID-19 done on oropharyngeal and nasopharyngeal swab on September 24, 2020 was positive . He was admitted in hospital for observation and managed with vitamin supplementation and hydroxychloroquin 200 mg twice daily for five days. He was subsequently transferred to institutional quarantine for two weeks. Saturation was maintained throughout and there was no need of oxygen therapy. His repeat RT-PCR done on oropharyngeal and nasopharyngeal swab was negative on October 8, 2020. After discharge, he was alright except for mild fatigue. He resumed the regular duties after being negative for COVID-19.After a week of COVID-ward duty, a 32 year old healthy medical doctor without any comorbidity developed mild fever with intermittent maximum temperature of 100° F associated with mild body ache. He did not have cough, shortness of breath, diarrhea, or taste or smell disturbance. His body mass index (BMI) was 26.67 kg/mAfter 25 days of having negative test of COVID-19, he again developed high grade fever with maximum temperature of 104° F associated with chills and rigor. He also had dry cough with no hemoptysis and no shortness of breath. He had diarrhea with passage of loose stool initially 2-3 episodes per day followed by more frequent stool after treatment with antibiotic. He had severe myalgia and weakness. Chest radiograph was normal. The presence of re-infection with COVID-19 was confirmed by RT-PCR  done on November 2, 2020. His nasopharyngeal swab for influenza virus was negative. He was managed with oral electrolyte solution, azithromycin 500mg daily, paracetamol and vitamins. However the fever continued with no relief with medication and he also developed severe headache, and asthenia. He was admitted in a hospital and treated with injection paracetamol and ceftriaxone, but the fever didn't subside. His blood sugar, urea, creatinine, and electrolytes remained normal. His Chest radiograph was normal. He maintained oxygen saturation between 94% and 97% on room air. However, his white blood cell count started increasing and related tests of inflammatory reactions also increased much .Rapid antibody detection test for COVID-19 was negative. His antibiotics were changed to injection meropenam, teicoplanin and doxycycline. Contrast enhanced computer tomography pulmonary angiography (CECT PA) done on November 6, 2020 showed normal CT pulmonary angiography, prominent lymph nodes in bilateral and subcarinal region, largest of which measures 10 mm, and bilateral minimal pleural effusion along with minimal linear fibrotic densities were noted in the right middle lobe, left lingual, superior, lateral basal and posterior basal segment of right lower lobe, superior, anteromedial basal and posterior basal segment of left lower lobe. There was no old CT chest available to compare. Injection Remdesivir was started, but it had to be stopped after three days due to transient AST and ALT elevations, to 203 and 227 respectively, and other deranged liver function tests with hypoproteinemia. His fever was continuous associated with chills and rigors for first 6 days which later became intermittent with relatively small spikes and by 10th day, he was afebrile. Diarrhea stopped at seventh day. His repeat nasopharyngeal swab for RT-PCR test done on November 8, 2020 was negative and he was discharged.He had insomnia and was very fearful and anxious for almost two weeks following discharge from hospital. He used to have vivid recall of memories of his stay in intensive care unit with deaths due to COVID-19 occurring around. His myalgia persisted for almost one month. Values of various biochemical tests became normal within one month on routine follow-up. He was depressed for nearly one month with loss of interest in study and work avoiding any news of COVID-19 and people. He joined his duty after one month of discharge. The cost of treatment during the reinfection of COVID-19 was around rupees three hundred thousand, which was almost 8 times his monthly salary. During the reinfection and recovery from the illness, he could not work for one and half month. Almost five months after discharge, he still gets anxious when he hears the news of arrival of second wave of COVID-19 and his co-workers getting infected.5 The pandemic due to due to the novel corona virus now known as severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) began since one and half year ago. The World Health Organization named the disease corona virus disease 2019 (COVID-19).6 Since the beginning of the COVID-19 pandemic, the issue of reinfection has been raised and discussed. We reported the case of a young medical doctor with COVID-19 reinfection in Nepal with more severe symptoms and higher cost of management. Thought most of the COVID-19 reinfections that have been reported have been milder than first encounters with the virus, reinfection can be severe and deaths have been reported.4It has been known that protective immunity is shortlived after seasonal corona viruses.7 our case also had worse disease than the first infection. There could be several reasons for more severe symptoms during reinfection. One risk factor of severe disease in our patient was high BMI of 26.67kg/m2 which was considered as obesity for Asian population.8 The other difference during infection and reinfection was the use of hydroxychloroquin during first infection only. There is no clear and well acceptable evidence of efficacy of hydroxychloroquine or chloroquine in the treatment of COVID-19.9 The data of frequency and severity of COVID-19 infection and disease in patients who were already receiving long term hydroxychloroquin or chloroquin for rheumatology and other indications may provide further evidence regarding their efficacy. Further it is speculated that those who experience the mildest symptoms in their initial infection may have a higher likelihood of reinfection, perhaps because they might not have developed adequate immune response the first time.1 This is consistent with the negative rapid antibody detection test for COVID-19 during the reinfection period in our patient who had milder symptoms during the first infection, though there are limitations of the rapid antibody detection test. Immunosuppressed patients may also not mount adequate immune response to the first infection and may be more susceptible to reinfection.1 Overall the occurrence of reinfection due to COVID-19 in the community remains a risk. However, even if reinfections are happening frequently in the community, the magnitude of reinfections may not be appreciated unless the studies are specifically designed to find out such problem.1Like the first confirmed case of COVID-19 reinfection in the USA,10 However our patient had negative RT-PCR test after the first illness due to COVID-19 and he had resumed normal activity for about four weeks when he had re-infection. The other related illness to consider is multisystem infammatory syndrome in adults (MIS-A). However MIS-A, like the multisystem infammatory syndrome in children (MIS-C), develops several weeks following confirmed or suspected COVID-19 infection and patients with MIS-A or MIS-C have negative RT-PCR test for COVID-19.10 In our patient, the RT-PCR test was positive during the reinfection period after becoming negative after the first infection with COVID-19. The third differential diagnosis to consider is reactivation of COVID-19 which is difficult to rule out. To certainly differentiate the reinfection from reactivation, the genomes of the viruses from both the samples collected during infection and reinfection would need to be shown to be different for it to be a reinfection.11 The large genomic structures of the COVID-19 could cause them to remain in the body at low enough levels to remain undetected which may be reactivated later.1 The fourth differential diagnosis is whether the reinfection is due to infection due to the new variants of COVID-19. Reinfection is likely due to the genetic drift in the COVID-19 such that the variant may elude the immune system in the body.1There are some differential diagnoses and conditions to consider in the case report. One differential diagnosis to consider is cytokine storm which a proportion of patients progress to at later stage of COVID-19.12 Vaccination should, thus, be done as per the availability and guidelines whether one is infected or not. However, COVID-19 infection may occur even after vaccination.13 The personal preventive measures like physical distancing, hand hygiene, wearing mask, and using personal protective equipment need to be considered by all whether one was infected or nor, or vaccinated or not. Apart from the personal preventive measures and vaccination, various measures that promote physical and mental health and may prevent occurrence of COVID-19 infection or its progression to complications should also be considered.14 Such health promotive measures which may prevent the occurrence of COVID-19 infection or its comorbidity and complications may not get adequate attention of the people unless they are emphasized by the national and global health agencies.14 Thus to prevent infection or reinfection due to COVID-19, vaccination and various personal preventive and health promotive measures need to be considered by all whether they are already infected, reinfected or vaccinated or not. Health care professionals are at high risk of getting COVID-19 infection and reinfection. Due priority needs to be given by the hospital management and other stakeholders to vaccination and such personal preventive and health promotive measures to protect the health care professionals.There are implications of COVID-19 reinfection to consider by the health professionals and others. Reinfection can happen. Reinfection can severely affect the person. Even if the symptoms are mild, they can transmit the infection to their family members or colleagues who can develop severe disease due to primary infection or reinfection. COVID-19 vaccine generates more consistent adequate immune response than COVID-19 infections.


Latent class analysis (LCA) categorized participants into three groups with different PFU levels: healthy users, moderate PFU users, and high PFU users. Hierarchical linear modeling (HLM) showed that the between-person level (class membership) accounted for most of the variability in psychological distress and well-being. No significant changes were found in psychological distress and well-being over time, but the High PFU users showed greater levels of psychological distress and lower levels of well-being at each time point. The findings of this study suggest that the relationship between PFU, psychological distress and well-being may reflect trait-like time-invariant differences between individuals rather than state-like changes.The social isolation and the subsequent, increased use of Social Networking Sites due to the COVID-19 pandemic have had an impact on subjective well-being around the world. The present longitudinal study examined whether changes in psychological distress and well-being during the Italian second wave of the pandemic differ among people with different levels of Problematic Facebook Use (PFU). A total of 493 participants (M In the last few years, the restrictions aimed at lessening the spread of the virus have resulted in social distancing, curfews, and shelter-in-place orders across the globe, all of which has led to limited interpersonal and close relationships. During this difficult time, people were overwhelmed by the continual desire to stay connected with others and improve interpersonal communication, and this need was easily satisfied by using social media, such as Facebook3. However, there is a debate on the consequences of heavy Facebook use for an individual’s well-being5, and whether problematic Facebook use (PFU), defined as a lack of self-regulation in one’s own use of Facebook, leading to problems in the user’s life7, can be conceptualized as dysfunctional behavior. Although Facebook might prove valuable in enhancing social contact, receiving positive feedback (there is no dislike button on this platform) and by enhancing social capital9, PFU is considered as a dysfunctional use of Facebook; it has been related to clinical impairments in various areas of one’s life, such as increased psychological distress and sense of loneliness, decreased self-esteem and life satisfaction13. Although PFU is associated with time spent online14, frequency of Facebook use does not seem to capture the core issues related to PFU15. Prior research adopted the broader construct of Problematic social media use (PSMU), which refers to an enduring preoccupation with social media  that can lead to impairment in well-being16 and/or nervousness, loneliness and other psychological problems17. However, focusing on specific social media platforms, such as Facebook, more than broad umbrella-constructs can be helpful to understand this complex phenomenon in more depth.The COVID-19 pandemic enhanced the individual’s use of social media and increased the risk of acquiring addictive tendencies15, but probably boasting distinctive features. For example, the hypothesis for passive social media use  posits that passive Facebook use can lead to a decline in well-being19. Recent reviews and meta-analytic evidence, from both cross-sectional and longitudinal studies, supported a negative association between passive social media use  and well-being outcomes20.Previous meta-analytic evidence showed that PFU is associated with excessive or problematic Internet use22. Contents posted by others are usually positively skewed, and social comparison can make readers feel negative about their own lives24. The meta-analysis by Yoon and colleagues25 showed that social comparisons on Facebook were more strongly related to depression than was the time actually spent, suggesting that an extensive use of SNSs might lead individuals to compare themselves with other users in a negative way, thus resulting in lower subjective well-being.Passive Facebook use might bring about negative feelings or distress because it may induce upward social comparison regarding dimensions that are important to one’s self-worth and social connectivity27. Problematic Facebook users experiencing unwanted feelings or a sense of loneliness when they use Facebook might report increased levels of FoMO29. Specifically, individuals who are afraid of being excluded from the world of Facebook and who are in situations of physical isolation might increase widespread use or PFU30.Prior research suggested that Fear of Missing Out  which are related to the individual’s need for relatedness, which may lead to lower well-being or distress. However, early research into PFU-well-being effects relied primarily on cross-sectional data6 and did not take into account how these effects varied in magnitude between individuals33. Thus, examining how PFU characteristics co-occur may provide a valuable research option. Prior research has utilized clustering techniques to identify distinct groups and patterns of problematic social media use37. In the current study we examine different patterns of PFU by Latent Class analysis (LCA) and whether these empirically-derived subgroups differ on both well-being and psychological distress over time. LCA derives a set of latent variables from a series of observed variables and allocates them to a latent class. Thus, this method can be useful in exploring the multifaceted nature of PFU and revealing its maladaptive patterns.To sum up, previous research suggested that the mental health consequences of SNSs such as Facebook may critically depend on the way they are used38, prior studies showed an association between problematic social media or passive use, online social comparison, FoMO with different facets of an individual’s distress during the first wave of the pandemic40. As previously mentioned, PFU takes place when the individual is characterized by a lack of self-regulation in one’s use, with negative consequences in daily activities, social relationships, and psychological health15. During the pandemic, problematic Facebook use appeared to foster home confinement41 and internet-associated risky behaviors42. Sayeed and colleagues43 identified several risk factors for the development of PFU during the Covid-19 pandemic, such as having relationship break-ups or a history of violence and stressful life events.In the present investigation we focus on the link between patterns of PFU and well-being during the COVID-19 outbreak, which has thus far not received extensive research attention. Although people have been using Facebook heavily for sharing COVID-19 informationHowever, it is worth noting that no prior longitudinal studies examined the relationship between patterns of PFU, well-being and distress during the second wave of the COVID-19 pandemic.45, it was hypothesized that the group with a higher dysfunctional pattern of PFU would have greater psychological distress and lower well-being across different stages of the second wave of pandemic.The present longitudinal study examined (i) whether distinct patterns of PFU could be identified through LCA on the basis of the following indicators: Facebook passive use, social comparison on Facebook, FoMO, and numbers of Facebook friends; and (ii) whether both moment-related evaluations, as well as changes in both psychological distress (i.e. depressive symptoms and Fear of COVID-19 pandemic) and well-being, differ among people with different patterns of PFU. According to prior evidence regarding positive associations between PFU and psychological distressage = 24.55 ± 7.25; age range = 18–63), 224  and 190  participants were considered for the three waves, respectively. Since we kept missing data points when matching the data for the three waves, the analytical sample included 493 participants. They were recruited through an announcement in the University and via on-line advertisements. Participation was voluntary and participants received no compensation. Information about the objectives of the study was given to the participants, and a prior statement of informed consent to participate was obtained from each participant. The online questionnaire took approximately 15–20 min to be completed. The research was conducted in accordance with the ethical standards of the Italian Psychological Association (AIP), as well as the Declaration of Helsinki. Participants’ demographic information and health-related data, as reported in Table Participants comprised college students at two large Universities in southern Italy. Four hundred and ninety-four participants consented to participate and completed an online survey at T0 . Of these, two hundred and twenty-four participants (response rate 45.3%) completed the survey at T1  and one hundred and ninety-one participants (response rate 38.7%) completed the survey at T2 . One participant was identified as a univariate outlier and was subsequently excluded from the analyses (see the Results section), thus 493 , psychological distress  and well-being were collected.At each wave, the first part of the questionnaire was used to collect information about participants’ demographic characteristics, including age, gender, educational level and marital status. In the next part, some questions about personal and relatives’ experiences of COVID-19 infection were inserted Iowa-Netherlands Comparison Orientation Measure (INCOM)47 is an 11-item self-report measure of social comparison orientation . For the purposes of the current study, the scale was adapted by asking participants to think about the social interactions and behavior that are established on Facebook . Items were rated on a 5-point Likert scale, from 1 (Strongly Disagree) to 5 (Strongly Agree) with higher overall scores indicating a greater Facebook Social comparison orientation40. The scale demonstrated good internal consistency in the present study at each time-point .The Active and Passive Facebook Use Scale (APUF)18 is a 7-item self-report measure of passive use of Facebook. Participants were asked to rate the frequency of use for some Facebook activities (e.g. “Reading posts”) on a 7-point Likert scale, from 1 (Never to) to 7 (More than once a day) with higher overall scores indicating a greater passive use of Facebook. The scale demonstrated acceptable-to-good internal reliability in the present study at each time-point .The Fear of Missing Out scale (FoMOs)48 is a 10-item self-report measure of fear of missing out (e.g. “I get anxious when I don’t know what my friends are up to”). Items were rated on a 5-point Likert scale, from 1  to 5 (Extremely true of me) with higher overall scores indicating more severe fear of missing out. The scale demonstrated good internal consistency in the present study at each time-point .The Depression, Anxiety and Stress Scale (DASS-21)50 was used to measure depressive symptoms (e.g.“I felt down hearted and blue”). Items were rated on a 4-point Likert scale, from 0 (It's never happened to me) to 3 (It's happened to me most of the time) with higher overall scores indicating more severe depression. The scale demonstrated excellent internal consistency in the present study at each time-point .The 7-item Depression subscale (DASS-D) of the Italian adaptation of Multidimensional Assessment of COVID-19-Related Fears (MAC-RF)45 is an 8-item self-report measure of fear of COVID-19 pandemic . Items were rated on a 5-point Likert scale, from 0 (Strongly Disagree) to 4 (Strongly Agree) with higher overall scores indicating more severe fear of the COVID-19 pandemic. In the present study, the scale demonstrated acceptable-to-good internal consistency in the present study at each timepoint .The Satisfaction with Life Scale (SWLS)52 is a 5-item self-report measure of well-being . Items were rated on a 5-point Likert scale, from 1 (Strongly Disagree) to 7 (Strongly Agree) with higher overall scores indicating a greater well-being. The scale demonstrated good-to-excellent internal reliability in the present study at each timepoint .The Data analyses were conducted using IBM SPSS (v. 22), Mplus (v. 7.0) and HLM software (v. 8.2). As a preliminary step in the data analysis, attrition analysis was conducted in order to compare participants with complete data with those with missing data at T1 and/or T2. Cronbach’s alphas were computed for all scales in order to assess their internal consistency. The normality of continuous variables was checked examining their skewness and kurtosis values. Descriptive statistics  were computed for demographics and variables of interest.53. Moreover, the clinical meaning of the latent classes was also considered when selecting the model.As a first step in the data analysis, Latent Class Analysis (LCA) was conducted in order to classify the participants into different groups according to their PFU  at T0. We ranked models containing the one to four latent class to find a more meaningful and parsimonious model. The following fit indicators were examined to determine how many groups should be classified: Bayesian information criterion (BIC), sample size adjusted BIC (aBIC), entropy, Lo-Mendell Rubin likelihood ratio test (LMR LRT), and bootstrap likelihood ratio test (BLRT). The most suitable model had the following fit indices: BIC and aBIC should be lower; entropy should be larger and LMR and BLRT should be significant54. Then, we entered the classes of participants -obtained through LCAs- as predictors of the longitudinal changes in psychological distress and well-being. This allowed us to test whether participants in specific classes experienced different time slopes compared to those from other classes. In addition, we compared the levels of each dependent variable at T1 and T2 across the classes through HLMs, changing how time was coded in our models  and testing for significant group differences at the Intercept.As a second step in the data analysis, we tested for the presence of significant linear changes in psychological distress  and well-being, from baseline to 4-months later, using 2-level Hierarchical Linear Models (HLMs). HLMs are considered one of the best statistical techniques for examining longitudinal changes in nested data255. Their magnitude was interpreted according to guidelines 56.Effect sizes indicating the proportion of within-person variance were accounted for by adding the linear parameter and were assessed and reported using pseudo-RThe study was conducted in accordance with the ethical standards of the Italian Psychological Association (AIP), as well as the Helsinki Declaration of 1975 and its later amendments. Informed consent was obtained from all individual participants to be included in the study.The study was approved by the Ethics Committee of the University of Palermo .At the baseline, no significant differences on demographics , health-related data , PFU characteristics , psychological distress  or well-being at T0 were found between participants with complete data on all waves and those with missing data at T1 and/or T2. Significant differences were found only for educational level and number of Facebook friends. The normality of continuous variables was checked, and a positive skewed distribution was found for the number of Facebook friends. One univariate outlier was removed, and square root transformation was conducted to improve the normality of this variable. All other variables revealed no substantial violation of normality regarding data distribution at each time point .n = 143; 29%) had the highest scores on all PFU indicators; therefore, it was defined as the “High PFU users”. Class 2  had the lowest scores on all indicators; therefore, it was defined as the “Healthy users”. Finally, Class 1  had indicators’ scores between Class 3 and Class 2; therefore, it was defined as the “Moderate PFU users”. Descriptives across all time points are reported in Table LCA identified three classes of participants. Evaluating one to four class models, the three-class model revealed the best solution Table . Class 3The 2-level HLMs models evidenced non-significant longitudinal changes in measures of psychological distress and well-being, from baseline to 4-months later. That is to say, participants from the entire sample did not experience significant changes in psychological distress nor in well-being over time. The addition of the predictor "Time" at level-1 of all models accounted for 17–33% of the within-patient variance in the dependent variables, with large effects (see Table ps < 0.05) in psychological distress  and life satisfaction . The only non-significant comparison was that between “Healthy users” and “Moderate PFU users” for fear of COVID-19. Interestingly, the grouping variable did not predict the longitudinal changes over time in psychological distress and well-being. That is to say, individuals clustered on the basis of their PFU pattern reported significantly different levels of psychological distress and well-being at baseline, which remained consistent over time . We further compared the levels of each dependent variable at T1 and T2 across the three classes; at two months follow-up, High PFU users reported greater levels of psychological distress and lower levels of well-being than the other two classes. Similarly, Moderate PFU users reported greater distress than Healthy users, but differences on well-being were not significant. At four months follow-up, High PFU users reported greater levels of psychological distress and lower levels of well-being than individuals belonging to the other two classes. Furthermore, Moderate PFU users reported greater fear of the COVID-19 pandemic than Healthy users, but all other comparisons were non-significant .We then added the dummy-coded grouping variables as second-level predictors in our models: at baseline (T0), participants from the three groups reported significantly different levels  led to almost identical results. Thus, our findings were robust in regard to the effect of these potentially confounding variables  may be less exposed to others' online content31. This may partially account for the higher scores for subjective well-being of users in the Healthy and Moderate PFU classes. The current findings further support the role of FoMO as an important facet of the individual’s impaired control with social media and as a correlate of psychological distress58.Consistently with our hypothesis , the findings of the study showed that participants with higher PFU also showed higher levels of psychological distress  as well as lower well-being at each time point. These findings support previous evidence regarding the association between PFU and psychological distress and the negative link between life satisfaction and PFU59, which exacerbated the use of SNSs for those who had already been problematic users before the pandemic. These findings may also explain the results regarding significantly lower levels of distress among both the Moderate PFU users and Healthy users during the second wave of the pandemic.During the second wave of the COVID-19 pandemic, it is also likely that the ongoing social restrictions may have increased PFU  and worsened subjective well-being60. Therefore, a vicious cycle may have been generated and subsequently a positive relationship with the PFU61. This leads to the speculation that people with more severe PFU may be more exposed to COVID-19 relevant information, and it may then result in exaggerated psychological distress62.Generally, social media-related activities may have been a major channel in the search for COVID-19-related information during the second wave of the pandemic32.The findings of the present study further indicated that the trajectory of psychological distress  and well-being across three stages of the second wave of pandemic remained stable for all the three classes. Thus, participants clustered as “High PFU users” reported significantly higher levels of depressive symptoms and fear of COVID-19 as well as lower levels of well-being, which remained consistent over time. Our results may suggest that the association between the severity of PFU, psychological distress and well-being may be related to stable trait-like and time-invariant differences between individuals (between-person variance) rather than state-like changes (within-person variance) which commonly refers to those that occur from one assessment point to the next oneThe current study extends our understanding of how PFU is associated with psychological distress and well-being by using a longitudinal design. Proposed implications are especially valuable when the relationship between COVID-19 pandemic, Facebook use, psychological distress and well-being is addressed. In addition, the results of the present study also included a period characterized by the easing of restrictions, which emphasized the importance of the potential need to maintain good mental health, even after the pandemic is over. However, some limitations should be considered when interpreting results. Firstly, the results may not be generalized to other countries due to discrepancies in the stage of COVID-19 infection and different governments’ policies aimed at limiting the spread of the virus. Secondly, the assessment of a non-stratified population with different recruitment procedures does not make these data generalizable. Thirdly, the self-report assessment may also limit conclusions from these results because the accuracy of the participants’ answers might have been affected. Future research needs to use a stratified sample whilst adding objective assessments of PFU.These results underlined the link between problematic Facebook use during the COVID-19 pandemic, psychological distress and well-being. It should be emphasized that increased time spent on social media was unavoidable during the pandemic when many activities were suspended. Therefore, in interpreting these results, one must be aware that, regardless of people’s usual online habits, the utilization of social media and information acquired through online activities may have triggered the onset of PFU, on top of general, increased internet use during the pandemic.Supplementary Information.


Societal restrictions due to COVID-19 have had a profound effect on our ability to connect with one another and limited our personal mobility. There is evidence that loneliness, social isolation, and psychological distress increased during restrictions for people with diabetes. Fluctuating restrictions provide a unique opportunity to utilise continuous GPS data from personal smartphones  to explore the relationship between time-at-home and psychosocial health for people with diabetes. This study aims to (1) describe the digital phenotypes of time-at-home during varying societal COVID-19 restrictions for people with and without type 2 diabetes and (2) to explore associations between these digital phenotypes and loneliness, social support, and other psychosocial factors and compare for people with and without type 2 diabetes.Data come from a longitudinal observational study in the Republic of Ireland that ran between March and August 2021. Participants are seventy-four adults  with (N = 40) and without (N = 34) diabetes. Continuous GPS data were recorded for 2 months through the Beiwe smartphone application. Loneliness (UCLA-3), social support (MSPSS), diabetes stigma  as well as other demographic, psychosocial, and lifestyle questionnaires were assessed at baseline, 1 month, and 2 months follow-up.GPS data are being processed. The GPS-derived features of time-at-home, overall movement, and location variance will be computed. Associations between these digital phenotypes and psychosocial factors will be explored and changes over time examined using multilevel modeling.We expect this study to be the first to describe and compare the digital phenotypes of people with and without diabetes during varying societal COVID-19 restrictions, providing new insights into the effects of such policies on the psychosocial health of people with diabetes.


Medical students are an at-risk group, with a greater incidence of anxiety2 than the general population, and a higher prevalence of suicidal ideation than physicians and nurses.3 The risk is further compounded by being young,1 having higher awareness of disease severity, and possessing common personality traits such as maladaptive perfectionism and difficulty adapting to disruption in routine.2The mental health of healthcare professionals has been significantly affected by the COVID-19 pandemic.4Medical students often face a sense of duty to volunteer in hospitals in times of global health emergencies such as the current pandemic, which can bring particular emotional challenges. The subsequent higher risk of transmitting COVID-19 may cause increased social isolation. Uncertainty around medical education due to cancelled exams and placements also increases stress.2 isolated studies worldwide have shown increased anxiety in those whose loved ones had contracted COVID-19 and who had interacted with COVID-19 patients.4Although a recent meta-analysis showed no difference in anxiety during COVID-19 in medical students,1 so more research must be done to identify those especially at risk. Those with pre-existing mental health issues have reported decreased access to the usual support services during the pandemic.1 To our knowledge, there is no available literature exploring the impact of COVID-19 on medical students with pre-existing mental illness. Experiences in previous pandemics such as SARS show that long-term mental health issues such as alcohol misuse and post-traumatic stress symptoms can persist for several years in healthcare workers who have been quarantined or have worked in high-risk areas.5Higher levels of baseline stress and depression are negative predictors of poor mental health,1The majority of current studies of mental health in COVID-19 have been cross-sectional, and few have focused on medical students. Longitudinal, large-scale, multi-country studies focusing on medical students of all age groups and investigating more variables, such as pre-existing mental illness, are required to identify those most at risk and the long-term effects on this population. The results of these studies could be used to improve future implementation of targeted medical student-specific mental healthcare interventions.


The lower bound of the 95% confidence interval (CI) of the geometric mean titer (GMT) ratio comparing MVC-COV1901 to AZD1222 was 3.4. The lower bound of the 95% CI of the sero-response rate was 95.5%. Both the GMT ratio and sero-response rate exceeded the criteria established by the Taiwan regulatory authority, leading to EUA approval of MVC-COV1901 in Taiwan.Rapid development and deployment of vaccines is crucial to control the continuously evolving COVID-19 pandemic. The placebo-controlled phase 3 efficacy trial is still the standard for authorizing vaccines in the majority of the world. However, due to a lack of eligible participants in parts of the world, this has not always been feasible. Recently, the Taiwan Food and Drug Administration, following the consensus of the International Coalition of Medicines Regulatory Authorities (ICMRA), adopted the use of immunobridging studies as acceptable for authorizing COVID-19 vaccines in lieu of efficacy data. Here, we describe a study in which our candidate vaccine, MVC-COV1901, an adjuvanted protein subunit vaccine, has been granted emergency use authorization (EUA) in Taiwan based on a noninferiority immunobridging study. Immunogenicity results from the per protocol immunogenicity (PPI) subset ( MVC-COV1901 is a protein subunit SARS-CoV-2 vaccine based on the stabilized prefusion spike protein S-2P adjuvanted with CpG 1018 and alum . It is aIn June 2021, experts from regulatory authorities around the world convened at a workshop for the future of COVID-19 vaccine development, and a consensus was reached for the use of well-justified and appropriately designed immunobridging studies in place of efficacy studies when they are not feasible . The resThe MVC-COV1901 phase 2 trial was a prospective, randomized, double-blind, placebo-controlled, and multicenter study to evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 vaccine candidate MVC-COV1901 NCT04695652) [95652 [6]For the MVC-COV1901 vaccine, the sample size was based on lot-to-lot consistency. The estimation was based on two-sided 95% CI [100(1 − 2α)%] calculated using the differences of the post-vaccination GMT of neutralizing antibody titers between a pair of lots. The total sample size and the size of each age subgroup was based on the minimum requirement of the TFDA. At the time of the study, there were no data available for the standard deviation of neutralizing antibody titers from AZD1222; therefore, the sample size for AZD1222 was not justified at the time the protocol was written. The trial protocol and informed consent form were approved by the TFDA and the ethics committees at the participating sites. The institutional review boards included the Chang Gung Medical Foundation, National Taiwan University Hospital, Taipei Veterans General Hospital, Tri-Service General Hospital, Taipei Medical University Hospital, Taipei Municipal Wanfang Hospital, Taoyuan General Hospital Ministry of Health and Welfare, China Medical University Hospital, Changhua Christian Hospital, National Cheng Kung University Hospital, and Kaoshiung Medical University Hospital. The trial was conducted in accordance with the principles of the Declaration of Helsinki and good clinical practice guidelines.10 viral particles. Both vaccines are delivered intramuscularly in the deltoid.MVC-COV1901 is a subunit vaccine consisting of the SARS-CoV-2 prefusion spike protein (S-2P) adjuvanted with 750 μg CpG 1018 and 375 μg aluminum hydroxide. A standard 0.5 mL dose contains 15 µg of the Spike-2P. The comparator vaccine is ChAdOx nCOV-19 (AZD1222), an adenoviral vector vaccine developed by University of Oxford, Oxford, United Kingdom and AstraZeneca, Cambridge, United Kingdom. Each dose of vaccine is 0.5 mL and contains 5 × 10Immunogenicity data: immunobridging study to evaluate the immunogenicity of a locally developed vaccine against a comparator vaccine which has already been approved in Taiwan.Safety data: at least 3000 subjects were required to be tracked for at least one month after the last dose and all subjects to be followed for a median of two months after the last dose.According to the TFDA, the following criteria were established for a candidate vaccine to be granted EUA in Taiwan :ImmunogeThe lower limit of the 95% CI of the geometric mean titer ratio (GMTR) of the prototype strain live virus neutralizing antibodies for the MVC-COV1901 vaccine group to the external control group must be greater than 0.67;The sero-response level  was defined as the proportion of subjects with neutralizing antibody titers against the prototype strain live virus at 60% of the reverse cumulative distribution curve for the external control group. The lower limit of the 95% CI for the sero-response rate must be greater than 50%.As AZD1222 was the first COVID-19 vaccine to be approved in Taiwan, it was chosen as the comparator vaccine for which the locally developed vaccines are to be benchmarked . The imm50 per 50 μL of virus and incubated at 37 °C for 1 h. After incubation, the mixture was added to Vero E6 cells and incubated at 37 °C in a 5% CO2 incubator for 4–5 days. The neutralizing titer (NT50) was estimated as the reciprocal of the highest dilution capable of inhibiting 50% of the cytopathic effect. The Reed–Muench method was used to calculate the NT50. Neutralizing antibody titers were then converted to the WHO Standardized Unit, IU/mL. The conversion was based on the WHO validated NIBSC reference panel. The GMT was derived from the results and converted to international units (IU/mL) [Neutralizing antibody titers against the Wuhan prototype SARS-CoV-2 strain were determined by a live virus neutralization assay performed in our phase 2 clinical study. The detection and characterization of neutralizing antibodies were performed by central laboratories using validated live virus neutralization assays. The live SARS-CoV-2 neutralization assay was performed as previously described with wildtype SARS-CoV-2, Taiwan CDC strain number 4  . BrieflyDescriptive statistics are presented for the population’s demographic and baseline characteristics. GMTs were estimated from neutralizing antibody titers measured at 28 days after the second dose of the study intervention. GMTR is calculated as the GMT of MVC-COV1901 group over the GMT of AZ1222 group.n [The GMTs are presented with their two-sided 95% CIs. Sensitivity analyses were performed by excluding elderly participants and those with elevated baseline neutralizing antibody levels. The most extreme modification of the dataset excluded participants with a GMT higher than the 67th percentile at day 57. Assessment of the magnitudes of differences in immune response between the two vaccines was conducted using an analysis of covariance (ANCOVA) model. The model included the log-transformed antibody titers at day 57 as the dependent variable, vaccine group (AZD1222 and MVC-COV1901) as an explanatory variable, and adjusted for age, body mass index (BMI), gender, and comorbidity profile. The 95% CI for the adjusted neutralizing antibody titers of each vaccine group were obtained. Then, adjusted GMT and corresponding 95% CI were back-transformed to the original scale. Lastly, to illustrate the strength of the immune response, reverse cumulative distribution (RCD) curves were constructed for data 28 days after the 2nd dose for the AZD1222 and MVC-COV1901 groups. As described by Reed et al. , RCD curn .All participants were of Asian descent. The mean age of the AZD1222 and MVC-COV1901 groups were similar but the MVC-COV1901 group had more elderly (>65 years old) participants . The AZDIn subjects under the age of 64, at 28 days after the second dose, the AZD1222 and MVC-COV1901 groups had GMTs of 186 and 733, respectively . When inIllustrated in The sensitivity analyses conducted to detect the robustness of GMT results reveal that both AZD1222 and MVC-COV1901 enhanced neutralizing antibody titers in both the subset of the younger individuals (aged 20–64 years) and the overall sample. The GMTR in the younger group  was comparable to the GMTR in the total population . The subgroup of younger individuals had higher GMTs compared to the overall GMTs for both vaccines. After adjusting for age, sex, BMI, and comorbidity status, the GMTR was similar in the total population and the younger age group . FindingMultiple regulatory agencies now consider that a primary endpoint of neutralizing antibodies induced by an investigational COVID-19 vaccine compared with those of a vaccine authorized based on efficacy is sufficient for approving new COVID-19 vaccines. The decision has become relevant as efficacy studies have become less feasible. Consistent with the recommendation by the International Coalition of Medicines Regulatory Authorities (ICMRA) , our stuThe neutralizing antibody titers were determined using World Health Organization (WHO)-certified reference standards, International Unit, IU/mL. The use of the standardized unit to report humoral immunogenicity could facilitate future cross-platform or cross-lab comparison. Moreover, since the participants in this study were mainly Asian, reporting our results in IU/mL can facilitate cross-ethnicity comparisons with other studies.MVC-COV1901 was well-tolerated without observed safety concerns in the phase 2 study . In addiResults of the study corroborate earlier findings, which suggest adenoviral vector vaccines generate lower neutralizing antibodies but, not examined in this study, higher T cell responses compared to protein subunit vaccines . For AZDThe most important limitation of this study is that it was a post hoc comparison of immunogenicity from two different studies. While the two studies were conducted at different times, both were conducted in the same clinical trial site, the AZD1222 study was conducted in one of the sites used in the phase 2 trial by the same investigators, using the same eligibility criteria. For example, those with previous known or potential exposure to COVID-19 were excluded in both studies. Additionally, cell-mediated immunity was not included in the comparative immunogenicity profile. Lastly, other characteristics of interest, such as waning immunity and cross-reactivity against variants of concern (VoCs), were not explored.The data presented in the study showed that it is reasonably likely that the vaccine efficacy of MVC-COV1901 is similar or superior to that of AZD1222. These data may have the potential to be used in support of further vaccine development and regulatory approvals.Immunobridging offers an alternative approach in cases wherein efficacy studies are not feasible. In this post hoc analysis, we have shown that MVC-COV1901, a protein subunit vaccine, elicits a comparable or superior immune response to that of AZD1222. This became the basis of its approval for an EUA in Taiwan. These findings have implications on the further development of vaccines for regulatory approval. In the long term, this approach may help improve the rate of vaccination and availability of vaccines, especially in low- and middle-income countries.