It is important to ensure that both the qualitative and quantitative aspects of clinical education are maintained during the pandemic. Understanding students’ views on clinical rotations and the extent of their perceived pandemic-related stress would thus be useful for designing and implementing effective clerkship programs. Therefore, this study aimed to investigate perceived stress and perceptions regarding clinical clerkship among incoming clinical students (third year) and senior clinical students (fourth year) during the COVID-19 pandemic.After completing orientation programs at the beginning of the academic year, we surveyed students on their perceived stress, their general perspectives regarding the appropriate scope of clinical clerkship, and their preferences regarding level of participation in clerkship. We examined the differences in stress and clerkship-related perceptions based on the students’ study year and sex using independent t-test, chi-squared test, and Fisher’s exact test. In addition, the influences of stress, sex, and study year on clerkship-related perceptions were examined using multinomial logistic regression.The independent t-test indicated that third-year students experienced lower stress than did fourth-year students. Clerkship-related perceptions also differed significantly between third- and fourth-year students. Multinomial logistic regression analyses on the scope of and participation levels in clinical clerkship revealed that third-year students had significantly lower odds of preferring a limited range of clinical rotations and lower engagement in clerkships compared to fourth-year students.The COVID-19 pandemic has affected clinical education and, consequently, medical students’ inclination toward active participation in clinical rotations. It is thus essential to understand students’ views and provide them with relevant intra-pandemic educational supports. The coronavirus disease 2019 (COVID-19) outbreak has interrupted and suspended various aspects of medical education and posed certain fundamental challenges in this regard  . This scAlong with academic challenges, varied pandemic-related impacts on personal and social activities have decreased well-being and increased mental health problems among students . ReporteThe clinical phase of medical education forms a critical period for students’ personal and professional development . They ofIn South Korea, most medical schools suspended clinical clerkships when the outbreak began in March 2020  but recoThe Institutional Review Board at Severance Hospital, Yonsei University Health System, approved this study as research using data obtained from normal educational practice in commonly accepted educational settings and thus considered to be an IRB-exempt study (IRB no. 4-2021-0351). Therefore, a waiver of informed consent was granted by the Institutional Review Board at Severance Hospital, Yonsei University Health System. All methods were carried out under the declaration of Helsinki, and the entire analysis was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for cross-sectional studies.A cross-sectional observational study involving third- and fourth-year clinical phase medical students was conducted at the Yonsei University College of Medicine, Seoul, South Korea. While the fourth-year students had experienced intra-pandemic core clerkships in the preceding year (2020), the third-year students had no clinical experiences before and were about to enter the clinical phase. Upon completing clerkship orientation programs at the beginning of the academic year, each student group received a survey for assessing their perceived stress and perceptions regarding clinical clerkships. Third-year students completed a paper-based survey between February 5, 2021, and February 9, 2021, while fourth-year students completed a web-based survey between February 27, 2021, and March 2, 2021. These periods corresponded to the cessation of the third wave of the COVID-19 outbreak in South Korea. Survey responses were obtained anonymously, and personally identifiable information was not collected.We used the perceived stress scale (PSS)  to assesWe asked students how they perceive the appropriate scope of clerkships during the COVID-19 pandemic, and they were prompted to choose from among the following statements:“Considering the current COVID-19 pandemic situation, what do you think is the appropriate scope of clinical clerkships?”Proceed with regular rotation schedule including emergency room (ER) and intensive care unit (ICU).Proceed with regular rotation schedule except for ER/ICU/isolation rooms.Carry out the clinical rotations in the general ward and outpatient clinic settings in small groups in a limited manner.Completely discontinue of all clinical rotations.As each response option reflects a distinct category, this variable was used as a nominal variable with four categories.The following questions and statements were used for assessing the students’ intra-pandemic perceptions regarding the appropriate participation level for clerkships:“Considering the current COVID-19 pandemic situation, what do you think is the appropriate participation level for clinical clerkships?”Actively participate in clinical rotations and COVID-19 pandemic-related volunteer work.Actively participate in clinical rotations but not in COVID-19 pandemic-related work.Participate only in essential clinical rotations for student safety (infection prevention).Minimize clinical rotations despite missing out on essential clinical rotations because students’ safety is the highest priority.Minimize clinical rotations, as students may be asymptomatic carriers.As each response option reflects a distinct category, this variable was used as a nominal variable with five categories.https://cran.r-project.org/), and the internal consistency of the PSS was measured with the R package psych. The multinomial logistic regression was performed with the R package mlogit. The level of statistical significance was set at α = 0.05.In this study, the descriptive statistics were presented as the mean and standard deviation for continuous variables and frequency and percentage for categorical variables. Independent-samples t-test and one-way analysis of variance were used to compare the students’ perceived stress based on study year, sex, and clerkship-related perception variables. The normality of data was examined with the Shapiro-Wilk test, and there was no violation of the normality assumption for proceeding with the independent samples t-test and analysis of variance. Chi-squared and Fisher’s exact test were used to analyze the associations between categorical variables, such as demographic factors and perceptions of the appropriate scope and participation levels for clinical clerkships. Furthermore, the possibility of the PSS score, sex, and students’ study year predicting clerkship-related perceptions was modeled using multinomial logistic regression. All analyses were conducted using the R software  for the third-year students and 58.0% (69/119) for the fourth-year students. We did not collect students’ age information; therefore, because of the responses’ anonymity, we could not identify their age after the survey. Regarding sex distribution, there was no difference between third-year and fourth-year students (p = 0.068) .The average PSS score of the entire sample was 14.63 (SD = 6.31), and 44.1%, 53.6%, and 2.2% of the students were identified as having low, moderate, and high levels of COVID-19-related stress, respectively. As shown in When analyzed based on sex, neither the score (p = 0.168) nor the stress level (p = 0.589) differed significantly . FurtherIn the total sample, 70.9% (127/179) of students preferred that regular clinical rotations should have proceeded, and 64.2% (115/179) of students opted for active engagement in clerkship, despite the pandemic’s impact. Most of the third-year students (51.8%) chose a regular rotation schedule , considering it to be the appropriate intra-pandemic scope of clerkship. Among the fourth-year students, the options of regular clinical rotations (except for ER/ICU/isolation rooms) and conducting rotations in general ward and outpatient clinic settings in a limited manner were the two most frequent responses (42.0% for each). Regarding appropriate participation levels for clerkship, third-year students most frequently responded that they would actively participate in clerkship activities and COVID-19-related volunteer work (38.2%). In contrast, fourth-year students chose participating in clerkship activities—but not in volunteer work—most frequently (39.1%). The detailed results are shown in We also analyzed whether students’ study year was associated with clerkship-related perception options. The distribution of the students’ responses to the appropriate scope (p = 0.005) and the level of participation (p = 0.007) differed significantly across the groups . On the 2 = 14.07, p = 0.029). As shown in 2 = 19.78, p = 0.019). Third-year students were less likely to select all types of limited clerkship participation compared to fourth-year students. The PSS score did not significantly predict the choice of clerkship participation level, but only for the most minimal clinical rotations compared to the reference category. The detailed results are shown in A multinomial logistic regression was conducted to model whether the perception toward clerkship could be predicted based on the PSS score, sex, and study year. As the last options of clerkship-related variables were rarely selected by students, we have combined the last two options of each variable into one category for analysis. The first options for each served as reference categories; this presents a broader spectrum of clerkship and a higher level of participation in clinical rotations. For the appropriate clerkship scope, the addition of predictors improved the model compared to the intercept-only model  that scores for burnout did not differ based on the preference to return to the clinical setting during the early phase of the COVID-19 outbreak. The multinomial logistic regression result aligned with this finding as the PSS scores did not predict the preferences for limited clerkship scope or engagement, except for choosing the most minimized engagement against the most active engagement. These findings altogether suggest that pandemic-related stress seems to have little impact on clerkship-related perceptions in general, while there remains a possibility that higher stress may lead to inclinations toward minimal clerkship participation during the pandemic.In the entire sample, the mean PSS score was 14.6, and more than half of the medical students were identified as having a certain level of COVID-19-related stress, among which about 2% of students were experiencing high levels of stress. Previous research findings involving the same instrument have shown that medical or health profession students’ perceived stress during the COVID-19 pandemic ranged from 17.8 to 20.4 . Based oet al. (2020), who also reported that third-year students were more likely to participate in clinical clerkship during the COVID-19 pandemic than fourth-year students in South Korea [et al.’s study was conducted in South Korea [et al.’s study and this study have a 1-year difference in the investigation timing, there is a similarity in terms of the academic calendar timing in that both surveys were conducted at the beginning of a new academic year. The third-year students starting their clinical clerkship may have been more motivated to pursue a broader clinical experience and active engagement in a new educational setting. Meanwhile, since fourth-year students in our study had gained more practical experiences about the impact of COVID-19 at the time of the survey, they may have encountered more clerkship challenges, thus growing to prefer more limited participation and range. However, these results should be interpreted with caution, as we did not investigate other personal and environmental factors that could have affected the students’ preferences for clerkship participation. A greater focus on factors that influence the students’ perception and morale, such as autonomous motivation, a higher sense of professional responsibility, and altruism [We have identified that more than half of the medical students in the total sample opted for regular clinical rotations and active participation in clerkship activities. In particular, third-year students entering the clinical phase were more likely to prefer clinical rotations involving high-risk departments for COVID-19 exposure, such as the ER and ICU, compared to fourth-year students, who had one year of prior clinical training. Similarly, third-year students preferred to be more involved in clinical activities, with most of them opting to volunteer in work related to the COVID-19 pandemic. In contrast, a higher proportion of fourth-year students chose to minimize clerkship participation compared to third-year students. These results correspond with the multinomial logistic regression finding that third-year students had lower odds of preferring a narrower scope for clerkship sites and more limited participation. Our finding was consistent with that of Kim th Korea . Howeverth Korea . This dith Korea , the strth Korea . Althougaltruism , 30, wouThis study had one major strength in that the options for breadth and depth of clinical clerkship were specifically described, which helped to build a concrete understanding of students’ preferences. Furthermore, as the study participants experienced an entire academic year under the influence of the pandemic, observing the waxing and waning of the situation, the study results may reflect stable preferences on this issue. However, despite the study’s strengths, there are several limitations that should be considered. The most important limitation lies in the fact that this study did not include other factors that could have affected the students’ distress and preference for clerkship activities and participation , 15, whiMedical students’ intra-pandemic perceived stress and perceptions toward clinical clerkship differed based on study year. Third-year students, who were starting their clinical clerkship year, reported lower stress and were more inclined to engage in clerkship activities compared to fourth-year students who had experienced prior clerkship. Given the importance of maintaining adequate quantity and quality of clinical education, it is important to critically reflect on educational experiences during the pandemic. Further studies that focus on the qualitative aspects of students’ clerkship experiences could help to discern the differential impacts of key factors and improve the clinical learning environment at a time of significant change. In addition, the development of a new curriculum and educational strategies that are suited for intra-pandemic changes in the clinical environment during the pandemic should be considered , 32.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


To this end, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and gene expression profiles were quantified. Results were correlated with transplant data and B-cell, and plasma cell infiltration was assessed by immunofluorescence microscopy. Both principal component analysis and clustering analysis of gene expression data revealed marked separation between LDs and DDs. Differential expression analysis identified 185 significant differentially expressed genes (adjusted p < 0.05). The expression of 68% of these genes significantly correlated with cold ischemia time (CIT). Furthermore, immunoglobulins were differentially expressed in zero-time biopsies from transplants later developing rejection (TCMR + ABMR) compared to non-rejected (Ctrl + DGF) transplants. In addition, immunoglobulin expression did not correlate with CIT but was increased in transplants with previous acute renal failure (ARF). In conclusion, gene expression profiles in zero-time biopsies derived from LDs are markedly different from those of DDs. Pre-transplant ARF increased immunoglobulin expression, which might be involved in triggering later rejection events. However, these findings must be confirmed in larger cohorts and the role of early immunoglobulin upregulation in zero-biopsies needs further clarification.Zero-time biopsies are taken to determine the quality of the donor organ at the time of transplantation. Histological analyses alone have so far not been able to identify parameters that allow the prediction of subsequent rejection episodes or graft survival. This study investigated whether gene expression analyses of zero-time biopsies might support this prediction. Using a well-characterized cohort of 26 zero-time biopsies from renal transplant patients that include 4 living donor (LD) and 22 deceased donor (DD) biopsies that later developed no rejection (Ctrl,  At the time point of kidney transplantation, many transplant centers routinely collect zero-time biopsies for determining graft quality, as a reference for later biopsies, and for gathering information with the potential to predict the later outcome after transplantation. However, the benefits of this practice are still under debate. Rathore et al. described that zero-time biopsies provide information regarding the general condition of the kidneys of the donors and that interstitial fibrosis and acute tubular injury in living donors (LDs) were significantly associated with allograft dysfunction . HoweverGiven that histological and immunohistochemical analyses have not yet identified parameters that definitely predict subsequent rejection episodes or graft survival, other analytic methods should be considered. Some gene expression analyses have shown that differences in the transcriptome of kidneys of the donors reflect graft function . Furthern = 7), delayed graft function , T-cell mediated rejection , or antibody-mediated rejection . For expression analysis, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and quantified with the NanoString Human Organ Transplant panel measuring the expression of nearly 800 genes. Genes with remarkable expression profiles regarding the different outcome groups were further analyzed.Here, we tested the hypothesis that expression profiles of transplant-related genes in kidneys of the donors can predict subsequent graft outcomes. To this aim, we examined the gene expression profiles of 26 zero-time biopsies from renal transplant patients who developed no rejection or dysfunction , ABMR (n = 7), and TCMR  within the first 2.5 years. Zero-time biopsies were taken as a protocol biopsy immediately before implantation of the graft into the recipient. Biopsies from patients with borderline changes or other co-morbidities, such as viral infection, immunoglobulin A (IgA)-nephropathy, or other immune-complex glomerulonephritis, were excluded. Neither patients from the control group nor from the DGF group developed a rejection or a borderline reaction at later stages. Zero-time biopsies from kidneys without signs of renal dysfunction or rejection after 1 year from transplantation served as controls . DGF was defined as impaired renal function necessitating dialysis within the first 10 days post-transplantation and lack of rejection. For the ABMR group, we included zero-time biopsies that later developed ABMR (active type II) with evidence of donor-specific antibodies (DSAs). Zero-time biopsies for the TCMR group were included if cases were developed later on after transplantation acute type IA, IB, or IIA TCMR without signs of ABMR. The study groups, characteristics of patients, and Banff classification are described for donors  were used to evaluate characteristic mRNA expression profiles in zero-time biopsies from patients who later developed DGF . 2O containing 111–393 ng mRNA and were concentrated using a Savant SPD111 SpeedVac (Thermo Fisher Scientific) at 35°C for 24 min to a volume of 2–3 μl. According to the recommendations of manufacturer, after a hybridization and preparation step, gene expression was analyzed with the NanoString nCounter FLEX Analysis System  using the nCounter Banff Human Organ Transplant (B-HOT) panel, containing 760 genes and 10 internal reference genes . RNA concentration and purity were measured with a NanoDrop Spectrophotometer , and isolates with a 260/280 nm absorbance ratio below 1.4 were excluded. All samples had a volume of 25 μl Hp was lower than 0.05. Principal component analysis was based on the variance-stabilized transformed counts of the top 100 variable genes. The expression heatmap was generated using standardized variance-stabilized transformed counts relying on the Complex Heatmap package v. 2.10.0. In order to perform functional enrichment analysis, first gene symbols associated with the NanoString nCounter® Human Organ Transplant Panel were mapped to Entrez Gene Ids relying on the biomaRt package v. 2.44.4 .To test for correlation between expression and CIT, Spearman’s rank correlation analysis was performed. Wilcoxon rank-sum test was used to assess differences in expression of selected genes between ARF and no ARF, an abundance of CD20- and CD138-positive cells between rejection and no rejection group, and to test for differences in age of the donor. A For immunofluorescence microscopy, 2 μm sections of FFPE kidney biopsies were utilized for the staining procedure. After antigen retrieval in target retrieval solution pH 6  for 2.5 min in a pressure cooker, sections were blocked in 1% bovine serum albumin diluted 1:50 in 50 mM Tris pH 7.4. Sections were then incubated overnight at room temperature with a mouse monoclonal antibody (IgG2a) against human CD20cy  together with a mouse monoclonal antibody (IgG1) against human CD138 , both diluted in blocking solution. After washing with 50 mM Tris pH 7.4, sections were incubated for 30 min with secondary antibodies: goat anti-mouse IgG1 conjugated with Alexa488  and goat anti-mouse IgG2a conjugated with Alexa633 . After additional washing, stained slides were covered with VECTASHIELD Vibrance antifade mounting medium containing 4′,6-diamidino-2-phenylindole (DAPI) for nuclear staining  and imaged on the slide-scanner Axio Scan.Z1 .Images of the scanned slides were evaluated with the software QuPath version 0.2.3 . ScannedHistopathological changes were graded according to the Banff classification score of 2013 and 2017 for renal transplant biopsies in the process of routine diagnosis , 19. Selp < 0.05) (p < 0.05) in samples later showing a rejection (TCMR or ABMR) versus samples showing no rejection (Ctrl or DGF).Histopathologic examination of the zero-time biopsies revealed no significant differences in kidney grafts with different outcomes . Therefo < 0.05) . Insteadp < 0.05). Fifteen of the 185 genes were assigned to this pathway , with the top ones being: GO: 0006911 phagocytosis, engulfment; GO: 0010324 membrane invagination; GO: 0099024 plasma membrane invagination; GO: 0006958 complement activation, classical pathway; GO: 0008037 cell recognition; GO: 0002455 humoral immune response mediated by immunoglobulin (While still adjusting for donor type (DD vs. LD), differential expression analysis was performed to compare samples developing rejection events later on to samples without rejection (controls and cases that developed DGF). In contrast to the high number of differentially expressed genes between DD and LD, only 11 genes were significantly differentially expressed in zero-time biopsies with later rejection . Interesglobulin .Since immunoglobulins were expressed by mature B cells and plasma cells, we evaluated the abundance of CD20-positive B-cells and CD138-positive plasma cells in FFPE sections of the zero-time biopsies using immunofluorescence microscopy. While in zero-time biopsies from Ctrl and DGF, CD20- and CD138-positive cells were detected only sporadically , in TCMRSince genes differentially expressed in rejection vs. no-rejection groups did not correlate with CIT, we investigated whether gene expression was correlated with other pre-transplant parameters. No correlation could be detected between gene expression levels and the need for reanimation or with the occurrence of sepsis in the donors (data not shown). In contrast, gene expression levels of 5 differentially expressed genes  were significantly associated with the occurrence of ARF prior to the explanation of the organs of donors and three more genes  showed a strong tendency toward this association .high, were found to play a protective role (After kidney transplantation, impaired kidney function due to DGF or rejection events, such as TCMR and ABMR, occurs on regular basis. At worst, this can lead to loss of the transplant. Graft loss due to these complications partly depends on factors related to the recipient but possibly also on the organs of donors. Suri et al. estimated that characteristics of donors account for 35–45% of the variability of early graft function . In the ive role . Interesive role . In prinive role . In ABMRive role . Interesive role  but was ive role . HoweverIn our study, transplant zero-time biopsies that later developed DGF showed comparable gene expression to controls or even a slight downregulation of transplantation-relevant genes, confirming similar observations reported by Hauser et al. . HoweverIn conclusion, this pilot study clearly showed that gene expression analysis can be performed using standard protocol zero-time biopsies without the need to take an extra biopsy for this purpose. We suggest that the expression of inflammation-associated genes in the transplant, already determined at the time of donation, at least in part influences the transplant outcome, which is already determined at the time of donation. Furthermore, the upregulation of immunoglobulin genes in zero-time biopsies may indicate an increased risk for subsequent rejection.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by The Ethics Committee of the Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.EV collected and analyzed the data, performed the experiments, and wrote the manuscript. SS analyzed the data and performed the experiments. MB-H collected and analyzed the data and edited the manuscript. KA collected data and edited the manuscript. EB edited the manuscript. JM-D and KH collected the clinical data. FF and MA analyzed the expression data and wrote the manuscript. CD initiated the study, collected and analyzed the data, and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cutaneous squamous cell cancer is a form of skin cancer, which is typically found in older fair-skinned individuals with frequent sun exposure. Most patients present with limited disease and can be treated with a combination of surgery and/or radiation with favorable outcomes. A small percentage of patients present with more aggressive, widespread disease. Immunotherapy has dramatically improved outcomes and has become the preferred treatment option for these patients. In this review article, the rationale for using immunotherapy in patients with squamous cell skin cancer is discussed. A summary of the new treatment options currently being explored is also provided.Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. A majority of patients present with localized disease, but some can present with locally advanced or metastatic disease. Most of these advanced cases occur in the anatomical head and neck region and are associated with more aggressive disease, necessitating prompt and effective treatment. Prior to the emergence of immunotherapy, systemic treatment options were limited to platinum-based chemotherapy and salvaged with targeted epidermal growth factor therapy. These therapies were associated with poor efficacy and increased toxicity in an often frail, older population. Immunotherapy has dramatically improved outcomes in this patient population due to its favorable side effect profile, durable treatment response, and improved overall outcomes. In this review, an overview of the recent advances of immunotherapy in the management of CSCC in the anatomical head and neck region is provided, with a focus on advanced presentations. Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer, and most cases develop in the head and neck anatomical area (HNCSCC) ,2. The mUntil the advent of immunotherapy, systemic therapies for HNCSCC were limited to cytotoxic platinum-based chemotherapy and salvaged with targeted therapy inhibiting the epidermal growth factor receptor (EGFR) . These tImmune checkpoint proteins serve as key regulators of the immune system’s response to cancer cells. T-cell activation requires a two-step process: (1) recognition of peptides via the T-cell receptor, and (2) interaction of coregulatory proteins (immune checkpoints) expressed on T cells, with partner proteins on tumor cells. Activation of these immune checkpoints may exhibit either stimulatory or inhibitory immune effects. Under normal circumstances, immune checkpoints ensure an appropriate immune response, while avoiding destruction of healthy tissue and immune hyperactivation as seen in autoimmune diseases. Programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are examples of immune checkpoints that have been studied extensively in cancer treatment. Upon activation, PD-1 and CTLA-4 deliver inhibitory signals to T cells resulting in T-cell inactivation. Immune checkpoint inhibitors (ICIs) block these proteins, resulting in an augmented anti-tumor immune response ,19.This review provides an overview of the recent advances of immunotherapy in the management of HNCSCC, with a focus on advanced presentations.For this review paper, the search terms “immunotherapy” and “cutaneous squamous cell carcinoma” were used in the PubMed database. The search revealed 375 papers published between the years 1971 and 2022. These were screened for eligibility. One duplicate record was removed. Only articles written in English and published within the last 10 years were included. Articles that did not involve adult human subjects were excluded. Forty-two articles not relevant to this topic were excluded. A total of 82 articles were included in this review .Cutaneous squamous cell carcinoma arises from uncontrolled growth of atypical keratinocytes, a major cell type found in the epidermidis . The curUV-B radiation is a major risk factor for CSCC development and has several detrimental effects on skin cells. It is absorbed almost completely within the epidermal skin layer. Exposure to UV-B radiation is responsible for promoting skin inflammation, and excess exposure can result in keratinocyte cell injury and apoptosis . UV-B raTreatment for CSCC is guided by whether lesions are considered low or high risk. Lesions involving the head and neck are considered high risk regardless of their size. For high-risk CSCC, Mohs micrographic surgery (MMS) is the preferred treatment modality . With MMIf negative margins are achieved following MMS, but extensive perineural involvement or other high-risk features are present, adjuvant RT is suggested. However, for CSCC cases that lack these features, continued cancer surveillance is offered every 3-to-6 months for the first 2 years, then every 6-to-12 months for the next 3 years, followed by annual skin exams. If positive margins remain following MMS, re-excision should be attempted. It this is not possible, RT and/or systemic therapy with immunotherapy should be considered .Upfront RT is indicated for HNCSCC patients who are considered poor surgical candidates (inoperable or patient preference) or if surgery is infeasible. Surgery may not be appropriate for the following reasons: (1) potential disfigurement or loss of function, (2) impossibility to obtain clear margins, and (3) older patients with multiple comorbidities . DefinitRadiation therapy could be indicated to reduce the risk of recurrence following surgery. As previously discussed, adjuvant RT is indicated for patients with positive margins following surgery (lesions that cannot be re-excised); recurrence following prior surgery with negative margins; lymph node involvement, especially if an extranodal extension is present; or presence of disease with perineural invasion . AdjuvanRadiation therapy is generally well tolerated. Potential RT-related toxicities are classified as acute (up to 6 months following RT) and delayed (greater than 6 months following RT). Acute toxicities manifest as skin reactions ranging in severity from redness to ulceration. Delayed toxicities can develop months to years following RT and are more frequently observed at higher dosages. Delayed toxicities may include changes in skin pigmentation, necrosis, atrophy, fibrosis, and secondary cancers .Finally, the use of RT is contraindicated for genetic conditions such as Li-Fraumeni syndrome or ataxia-telangiectasia, which predispose patients to increased RT toxicity. Connective tissue disorders such as scleroderma are a relative contraindication due to the potential risk for RT-induced fibrosis and worsening of symptoms . Given tThere are no standardized chemotherapy regimens for the treatment of locally advanced or mHNCSCC. Chemotherapeutic agents that have been studied include platinum agents (cisplatin or carboplatin), 5-fluorouracil, bleomycin, doxorubicin, methotrexate, and taxanes. The most-utilized treatment strategies have been platinum agents, used as mono- or combination therapy. Chemotherapy efficacy data has been mostly limited to small observational studies with varying responses . One ranEGFR inhibitors have been investigated extensively and represent a molecular target for the treatment of advanced HNCSCC. EGFR overexpression has been demonstrated in HNCSCC and may be associated with a poor prognosis . EGFR inAn additional molecular target currently being explored in HNCSCC is the mitogen-activated protein kinase/ERK kinase (MEK) pathway, which is downstream from the EGFR pathway. A phase II study is investigating the combination of MEK inhibitor cobimetinib with atezolizumab in patients with advanced tumors, including CSCC. Results of this study (NCT03108131) have not been published yet.Another molecular target is the VEGFR, which is believed to contribute to EGFR resistance. A phase I study investigating lenvatinib, a tyrosine kinase inhibitor of the VEGFR, in combination with cetuximab for advanced HNCSCC was recently completed (NCT03524326); the results have not been published.Finally, the PI3K/AKT/mTOR downstream EGFR signaling pathway represents another promising therapeutic target for CSCC . LY30234The first immunotherapy drug used for the treatment of CSCC was intralesional interferon . Over thUnder normal circumstances, the immune system acts as a natural defense against cancer. The strength of immunosurveillance is primordial to prevent cancer growth. The healthy immune system operates in an elimination mode, by recognizing tumor-specific antigens, eliminating cancer cells, and preventing tumor growth. The immune system and tumor may enter an equilibrium mode, in which the cancer is allowed to persist without growing. An unhealthy immune system allows mutations to arise, and subsets of cancer cells then evade immune detection because of the dampened immune system’s antitumor response. This is known as the escape mode, which allows for uncontrolled cancer growth and progression ,52. ExamAdditionally, patients with advanced HNCSCC typically exhibit high TMB, a majority of which are caused by UV radiation exposure . As prevLocally advanced HNCSCC is defined as a tumor that is no longer amenable to curative surgery or RT, or could lead to severe anatomical dysfunction when treated with surgery and/or RT . Such agIn the following section, we describe the results obtained in well-designed clinical trials of modern immunotherapy agents.Cemiplimab is a monoclonal antibody that targets PD-1. It was the first anti-PD-1 drug to be FDA approved for frontline management of patients with locally advanced or metastatic CSCC . CemipliPembrolizumab is a monoclonal antibody that targets PD-1. It is approved for frontline management of patients with recurrent, metastatic, or locally advanced HNCSCC that cannot be cured with surgery or RT . PembrolIn the investigator-initiated CARSKIN trial, treatment-naïve patients with advanced CSCC were enrolled and treated for up to 2 years. The ORR was 42%, CR was 7%, and PR was 35%. Additionally, the ORR was significantly greater (55%) among patients with PD ligand-1 (PD-L1) positivity, compared to patients with PD-L1 negative tumors (17%). In the primary cohort patients who were treated up to week 15, the ORR was 41%. None of the patients recurred during the follow-up observation period of 22.4 months. One developed a new primary HNCSCC. Finally, the median PFS and OS were 29 weeks , 15 weeks–NR) and 108 weeks , respectively . InteresPresently there are no predictive ICI biomarkers to assess whether patients are responding well to treatment or to guide decision making for patients with HNCSCC . ResponsThe role of TMB as a predictive biomarker for HNCSCC patients remains unclear. A study published by Goodman et al. involving SCC patients concluded that 2 characteristics, cutaneous origin and higher TMB, correlated with improved outcomes for PD-L1 blockade . HoweverNot only are immunocompromised patients at increased risk for HNCSCC, but immune status has been demonstrated to negatively affect disease outcomes. A multicenter study by Manyam et al. showed significantly lower locoregional recurrence-free survival (47.3% vs. 86.1%) and PFS (38.7% vs. 71.6%) in immunosuppressed compared to immunocompetent patients . A retroAdditionally, in the SOTR patient population, the type of immunosuppressant used may influence the development of CSCC. Calcineurin inhibitors are known to increase the likelihood of CSCC development ,76. In oFinally, immunotherapy clinical trials have historically excluded SOTR patients, due to the possibility of graft rejection following ICI-induced immune activation. Therefore, a risk-benefit discussion should take place with SOTR patients before starting immunotherapy because of the significant potential for allograft rejection, resulting in the need for dialysis and/or death . CurrentCurrently, there are no approved ICI drugs for treatment of HNCSCC in the neoadjuvant or adjuvant setting. Clinical trials are ongoing, investigating the use of ICIs  prior to surgery. However, risks associated with this approach include a delay in surgical treatment, which may result in an unresectable tumor and increase the risk of adverse events. In a study by Ferraroto et al. involving 20 patients with recurrent and resectable stage II-IV HNCSCC, 2 cycles of cemiplimab prior to surgery resulted in 11 pathologic CRs and 3 major pathologic responses . A folloPrevious studies in metastatic melanoma patients demonstrated that lower disease burden was associated with an increased likelihood of survival following treatment with PD-1 inhibition ,81. BaseNovel treatment approaches are needed to improve outcomes in patients with HNCSCC and to overcome drug resistance . These aWhile not officially approved for use in patients with non-melanoma skin cancer, other ICIs may be effective in treating patients with advanced CSCC. Their efficacy thus far has been limited to published case reports and case series.Nivolumab, a monoclonal antibody targeting PD-1, was assessed in 3 patients with recurrent CSCC who had previously been treated with chemotherapy. A PR was noted in 2 patients, and 1 patient experienced stable disease following 3 months of treatment . Chen etIpilimumab is a CTLA-4 inhibitor approved for use in metastatic melanoma patients. Similar to nivolumab, its efficacy has been limited to published case reports. Day et al. described a patient with metastatic CSCC, previously treated with chemotherapy, who achieved a CR following 4 cycles of ipilimumab . We haveAnother innovative strategy is the combination of immunotherapy with RT. Radiation-induced damage to cells has several effects on the immune system, including T-cell priming and upregulation of immune checkpoint molecules on tumor cells, which in turn can facilitate increased immune-mediated cell death when combined with ICIs . This trThe I-TACKLE trial—an open-label, nonrandomized, phase II trial in 43 patients with locally advanced or metastatic CSCC conducted in 3 Italian centers—investigated the addition of an anti-EGFR agent cetuximab to pembrolizumab to counteract pembrolizumab resistance. Forty-four percent of patients experienced a response to pembrolizumab with a cumulative ORR of 63%. Twenty-one patients had primary resistance to pembrolizumab and received the combination therapy . The addOncolytic viruses (OVs) are injected into tumors and exert both local and systemic antineoplastic effects within the body. Locally, OVs selectively infect and grow within the injected tumor, resulting in tumor lysis and cell death . Tumor lRP1 is a genetically modified herpes simplex OV. Niu et al. reported promising results in the phase I/II IGNYTE trial, in which patients with HNCSCC and other tumor types achieved a CR rate close to 50% when treated with RP1 monotherapy or in combination with nivolumab. Tumor regression was observed in both injected and non-injected distant lesions following RP1, suggestive of a systemic treatment response . A phaseTalimogene laherparepvec (T-VEC) is another genetically modified herpes simplex OV currently being studied in CSCC. A recent phase II study interim analysis reported 100% ORR in 7 patients with low-risk CSCC treated with T-VEC . OngoingTwo studies are investigating the use of photoimmunotherapy in the treatment of patients with CSCC. This involves the injection of an antibody-dye conjugate, followed by activation with a particular wavelength of light. RM-1995 is composed of an antibody that targets CD25, a receptor with increased expression by regulatory T cells (Treg). This drug conjugate is activated when illuminated by red light, and targets Treg cells within tumors, thus augmenting the antitumor immune response. RM-1995 is given as a single agent as well as in combination with pembrolizumab (NCT05220748). In the other study, ASP-1929 is composed of an EGFR antibody that is also activated by the illumination of red light. ASP-1929 will be given in combination with cemiplimab (NCT04305795).Another study is exploring the use of an intra-tumoral vaccine injection expressing a DNA plasmid known as IFX-Hu2.0 (NCT04160065). This results in expression of a streptococcal membrane protein within the lesion, which in turn stimulates the immune system and produces a favorable environment for ICI therapy. This phase I study plans to enroll 20 patients with advanced non-melanoma skin cancers .Additionally, B7-H3 has emerged as a promising molecular target for immunotherapy-based studies. It is an immune checkpoint protein, which exerts inhibitory effects on the immune system via suppression of T-cell activation and proliferation. It is highly expressed in various solid tumors, yet has limited expression in normal tissues. Increased B7-H3 expression has been shown to promote immune escape and tumor growth in head and neck squamous cell carcinoma (HNSCC) stem cells . FurtherFinally, several studies are exploring the use of cytokines in combination with immunotherapy, including one phase IB/IIA study evaluating the use of interleukin-7 (IL-7) in combination with atezolizumab in patients with advanced cutaneous malignancies (NCT03901573). IL-7 is critical for the development of naïve and memory T cells, which in turn facilitate an antitumor immune response . CSCC is common, and most cases are diagnosed at an early stage and associated with a favorable prognosis. Advanced-stage presentations are rare but require multidisciplinary care due to the complexity of the disease, the patients’ comorbidities, and the need for systemic treatment in an often-frail older population. Immunotherapy has transformed the care of advanced or mHNCSCC patients due its favorable side effect profile, durable treatment response, and improved OS rates. Anti-PD-1 drugs remain the backbone of clinical investigation, and new combinations are being tested, including the co-administration of RT, EGFR antagonists, or OV. Additionally, the activity, efficacy, and safety of anti-PD-1 drugs are currently being evaluated in the neoadjuvant and adjuvant settings for patients with advanced CSCC .


Although frequently used in the early pandemic, data on the effectiveness of COVID-19 convalescent plasma (CCP) remain mixed. We investigated the effectiveness and safety of CCP in hospitalized COVID-19 patients in real-world practices during the first two waves of the pandemic in a multi-hospital healthcare system in Texas.Among 11,322 hospitalized patients with confirmed COVID-19 infection from July 1, 2020 to April 15, 2021, we included patients who received CCP and matched them with those who did not receive CCP within ±2 days of the transfusion date across sites within strata of sex, age groups, days and use of dexamethasone from hospital admission to the match date, and oxygen requirements 4–12 hours prior to the match date. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effectiveness outcomes in a propensity score 1:1 matched cohort. Pre-defined safety outcomes were described. We included 1,245 patients each in the CCP treated and untreated groups. Oxygen support was required by 93% of patients at the baseline. The pre-defined primary effectiveness outcome of 28-day in-hospital all-cause mortality  were similar between treatment groups. Sensitivity and stratified analyses found similar null results. CCP-treated patients were less likely to be discharged alive , and more likely to receive mechanical ventilation . Safety outcomes were rare and similar between treatment groups.The findings in this large, matched cohort of patients hospitalized with COVID-19 and mostly requiring oxygen support at the time of treatment, do not support a clinical benefit in 28-day in-hospital all-cause mortality for CCP. Future studies should assess the potential benefits with specifically high-titer units in perhaps certain subgroups of patients (e.g. those with early disease or immunocompromised). Transfusion of convalescent plasma (CP) is frequently proposed as passive immune therapy for emerging viral infections, including during the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 . Based oWhile RCTs provide more definitive evidence of treatment efficacy, analyses of the real-world use of CCP in large cohorts may offer insight into clinical effectiveness, and reasons for differences across observational studies, including assessment of concomitant therapies. Identifying factors potentially associated with the clinical benefit, or lack thereof, can inform further analyses of RCT data, assist in future trial designs, and provide valuable information for the use of CP in future emerging infectious diseases. Finally, methods used to control for confounding can inform future assessment of real-world evidence, especially in emerging pandemics. Herein, we report associations between CCP treatment and effectiveness outcomes, and describe safety outcomes following transfusion in a multi-hospital healthcare system in Texas from July 2020 to April 2021.online. This study was reviewed and approved by the Baylor Scott & White Research Institute Institutional Review Board, with a waiver of the requirement for informed consent.This retrospective cohort study analyzed data extracted from the Epic electronic health record (EHR) system from 25 acute care Baylor Scott White & Health (BSWH) hospitals across north and central Texas from July 1, 2020 to April 15, 2021 . The proPatients who had a positive RT-PCR test for SARS-CoV-2 infection within 14 days of hospital admission were identified for risk-set sampling. Among these patients, we included patients who received CCP and those who did not receive CCP within four days (± 2 days) of the transfusion date during the study period across sites. Prior to August 23, 2020, patients in the study received CCP under INDs, largely through the national EAP, while patients treated after August 23, 2020, may have received CCP under EUA or IND. Eligibility for treatment under either regulatory pathway included hospitalized patients with COVID-19, and transfused patients in this study were therefore expected to include a heterogenous mix that reflected real-world practice at the time. The heterogeneity of clinical characteristics applied to the untreated group as well. Matching on calendar date was conducted to account for the potential period effect as the standard of care changed quickly for hospitalized COVID-19 patients with the evolving pandemic. The transfusion date or the match day was defined as the index date. We matched each CCP recipient to up to four untreated patients on sex, age (±5 years), days from hospital admission to index date, oxygen requirements 4–12 hours prior to index date, and use of dexamethasone from admission to index date. Specific definitions of oxygen requirement strata  are provided in the publicly posted study protocol and generally reflect low versus high flow oxygen requirement  transfer, and mechanical ventilation. We identified date of death and discharge status for in-hospital mortality and discharge alive status. ICU transfer was defined as EHR transfer entries in and out of ICU departments, or ICU accommodation codes. Mechanical ventilation was identified by reviewing the oxygen therapy flowsheet for the physician-defined treatment types that met criteria.Safety outcomes related to plasma transfusion were explored, selected from the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance Protocol, and identified with International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM)  or mean and standard deviation (SD) for continuous variables, as appropriate.To account for confounding by baseline covariates, we conducted one-to-one nearest neighbor propensity score matching without replacement using a caliper of 0.25 and exact match on age (±2.5 years), days from hospital admission to the index date, oxygen support 4–12 hours prior to the index date, and use of dexamethasone from admission to the index date between exposure groups. Absolute standardized differences were computed for each baseline covariate to check its distribution balance between exposure groups pre- and post-propensity score matching. We also visually inspected overlaps between density plots of post-propensity score matching Fig 1 in .Crude and adjusted incidence rates for all-cause in-hospital mortality in the first 7, 14, 21, and 28 days from the index date were estimated pre- and post-propensity score matching, respectively. Cumulative incidence curves for in-hospital mortality were depicted for each exposure group and compared using the log-rank test. Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using the post-propensity score matched cohort for effectiveness outcomes, with hospital site included as the random effect. Hospital site was not included in the propensity score model to preserve the degree of freedom, given the number of other covariates and the sample size. For the primary effectiveness outcome, patients were followed from the index date until the earliest of death, discharge alive, or day 28 from the index date . The proportional hazards assumption was evaluated using Schoenfeld residuals test and visual inspection of log-log plots. Given the rarity of the safety outcomes, we only reported frequencies and proportions of these among patients who received CCP in the post-propensity score matched population.To evaluate the robustness of the effectiveness results, we conducted following sensitivity analyses for all pre-defined effectiveness outcomes: 1) restricting to a subset of patients admitted to the hospital within ±7 days of RT-PCR confirmed COVID-19 diagnosis; 2) following patients up to the end of the study period; and 3) estimating sub-distribution hazard ratios using the Fine‐Gray model to account for the competing risk between in-hospital mortality and discharge alive. To further evaluate the CCP effectiveness, we conducted the following subgroup analyses for the pre-defined primary effectiveness outcome: 1) stratifying mechanical ventilation status prior to or at the index date; 2) restricting to patients receiving remdesivir prior to or at the index date; 3) stratifying the time interval from hospital admission to the index date (<72 versus ≥72 hours); and 4) stratifying oxygen support 4–12 hours prior to the index date.Secondary outcomes  were also analyzed to evaluate CCP’s effectiveness on disease progression. Analysis of these outcomes was performed in the same manner as the primary outcome.P-value of <0.05 was considered statistically significant. Missing values were coded as a separate category for each covariate and included in the analyses. No adjustments were made for multiple testing.All statistical analyses were conducted with SAS 9.4 and R 3.5.1. A two-sided Risk-set sampling resulted in an even distribution of dexamethasone treatment in the pre- and post-propensity score matched cohorts with 99% of patients receiving it in the post-propensity score matched cohort. Propensity score matching improved imbalance in some comedications with absolute standardized differences <0.1; 90% of patients received anti-thrombotic drugs, 70% received remdesivir, and over 50% received azithromycin in each exposure group.Proxies for COVID-19 disease severity before and after propensity score matching are also presented in There was a single transfusion associated circulatory overload (TACO) incident in the CCP-treated group (Table 3 in P = 0.308).In-hospital mortality incidence rates (IRs) for both pre- and post-propensity score matched cohorts are given in Table 4 in P = 0.190) and the interaction term of log(time) and treatment in the Cox model (P = 0.295). Similar null findings were also observed in sensitivity analyses, when 1) restricting the analytic cohort to a subset of patients admitted within ±7 days of RT-PCR confirmed COVID-19 ; 2) allowing follow-up to continue until the end of the study period ; and 3) considering the competing-risk of discharge alive .Cox proportional hazards modeling found no statistically significant difference for 28-day in-hospital mortality  between CCP-treated and untreated patients . ProportStratification by mechanical ventilation status at the index date found no statistically significant difference for 28-day in-hospital mortality between CCP-treated and untreated patients . Only a Compared with untreated patients, CCP-treated patients were less likely to be discharged alive up to 28 days after index date , and more likely to receive mechanical ventilation  . These rOur study reports results from a large, matched cohort of hospitalized COVID-19 patients and did not find a clinical benefit in in-hospital 28-day all-cause mortality for CCP-treated compared to non-treated patients. Our study assessed the effectiveness of CCP in a population consistent with real-world clinical practices over the first two waves of the pandemic in Texas   and the Rates of key safety events were similar between exposure groups, and transfusion-associated adverse events were rare, with only one TACO episode reported in the transfused group. Considering the incidence of transfusion-associated adverse events  was lower than typically reported for plasma transfusion in hospitalized and critically ill subjects –12, thesEvidence of CCP’s role in the treatment of COVID-19 remains mixed. Heterogeneity of clinical practice, clinical characteristics of patient populations, and product characteristics, in addition to the evolving pandemic and concurrent clinical management, complicates the interpretation of meta-analyses –15. SeveThe observed lack of effect in COVID-19 patients in this study should be considered in the context of the anticipated importance of timing of passive immune therapy . The high proportion of subjects already requiring oxygen support (>90%), suggests that many patients would have been more than a week into symptomatic illness  and thata priori power calculations to detect a relative risk of 0.80. As evidenced by the characteristics summarized in Strengths of the current study include a large sample size selected with The current study has notable limitations. First, our study lacks anti-SARS-CoV-2 antibody titer information in the transfused CCP, either via serologic or neutralization testing, which is likely to impact potential effectiveness of the transfused CCP. Nonetheless, as availability of such tests remained limited during the study period  and implIn summary, our study did not find a reduction in 28-day in-hospital all-cause mortality in a large cohort of hospitalized patients treated with CCP compared with those untreated with CCP in a multi-center hospital system in Texas. The results should be interpreted in the context of both strengths and limitations of this study, which, while reflecting real-word use of CCP, include a heterogeneous hospitalized patient population largely requiring oxygen support, a lack of data on the antibody titer in the transfused CCP and on the serostatus of patients prior to transfusion. These results can help prioritize future studies and inform the potential role of CP in future pandemics, or in the context of emerging variants, where the rapid availability of CCP, some with ability to cross-neutralize variants , supportS1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


Recent studies on patients with muscle-invasive bladder cancer (MIBC) undergoing neoadjuvant chemotherapy (NAC) have shown an association between NAC and thromboembolic events (TEE) prior to radical cystectomy (RC). Recent studies suggest that central venous access catheters (CVAs) may induce TEEs, and low-molecular-weight heparin (LMWH) has been mentioned as possible prophylaxis. However, other studies have shown a high incidence of decreased renal function in these patients. The purpose of this study was to determine the portion of MIBC patients with NAC-induced TEEs who had decreased preoperative renal function for whom LMWH potentially would not be beneficial as prophylaxis. We identified 459 cystectomized MIBC patients from two Swedish medical centers from 2009 to 2021. The inclusion criterion of cT2-T4aN0M0 resulted in 220 eligible patients, who were further divided into NAC-administered (n = 187) and NAC-eligible (n = 33), the tentative control group. Values of renal function before, during, and after each NAC cycle were retrospectively collected from individual medical records. Amongst the NAC-administered patients with TEE (n = 29), 41% (95% CI 23.5–61.1%) of patients had decreased renal function. Thus, a substantial portion of NAC-administered patients who developed TEEs had reduced renal function and would have been less likely to have benefited from renal clearance-dependent LMWH prophylaxis. Urinary bladder cancer accounted for around 570,000 new cancer cases and about 200,000 deaths worldwide in 2020, making it the tenth most commonly diagnosed cancer . BladderThe NAC regimen for MIBC patients in Sweden in most centers consists of a cisplatin-based combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), while in patients who are ineligible for cisplatin, a carboplatin-gemcitabine combination is used . EligibiThe study population was derived from an extensive dataset based on records of radically cystectomized patients with urothelial carcinoma in the urinary bladder in the years 2009–2021. Patients’ data were retrospectively collected from individual medical records from the two participating Swedish centers: Norrlands Universitetsjukhus in Umeå and Länssjukhuset in Sundsvall. The inclusion criteria allowed for MIBC carcinomas categorized as cT2-T4bN0M0 with urothelial or mixed-type histopathology, thus excluding non-muscle-invasive cancers, disseminated disease before treatment initiation, and histopathology without any urothelial component. Hence, of the 459 radically cystectomized patients who were initially available for consideration, 220 were suitable for analysis, as 239 patients were excluded due to unfit histopathology, non-cT2-4aN0M0, or not fulfilling the criteria for NAC treatment and thus being deemed as non-NAC-eligible patients. For detailed information on patient selection, see The majority of MIBC patients in Sweden today receive 3 or 4 cycles of chemotherapy before RC, and in 2021, 71% of all MIBC patients received NAC in Umeå. On the contrary, in 2009, only 17% received NAC in Umeå, as NAC was not recommended by clinical guidelines until more recent years. Hence, a portion of all MIBC patients in Sweden did not receive NAC and was solely radically cystectomized. As chemotherapy by time was introduced into modern MIBC guidelines, the number of NAC-administrated patients rose. However, a few patients still are untreated due to other circumstances; for example, some choose to reject NAC. Thus, non-NAC but NAC-eligible patients provide us with a suitable parallel control group, as these patients can be regarded as exhibiting the same clinical status as those treated with NAC . Consequor without reduced kidney function. As one patient could potentially have either one single or several pathological values, multiple groupings regarding the type of measurement of kidney function at different time periods were considered.Laboratory values regarding renal function were gathered, adding to the database’s already large collection of clinicopathological variables, such as age, gender, smoking habits, BMI, ASA, CACI, and TEE. Values for renal function are monitored in MIBC patients but are rarely measured by one single variable. Thus, four measurements were obtained for the study to obtain a conclusive portrayal of each patient’s clinical kidney status: serum/plasma creatinine (S/P-creatinine), eGFR by cystatin c, eGFR by creatinine and chrome-ethylenediaminetetraacetic acid (Cr-EDTA). The cut-offs for each measurement were in accordance with Swedish clinical practice and the standardized reference intervals: S/P-creatinine > 90 for females and > 100 for males, eGFR (creatinine) < 60, eGFR (cystatin c) < 60, and Cr-EDTA < 60. The reference intervals for all analyzed measurements are presented in Another distinction in the study cohort was made by separating the NAC-administrated who did or did not suffer a TEE. The TEE incidences, presented in Population characteristics for interval variables are described as means and standard deviation, and those for nominal variables are described as frequencies and percentages. The confidence interval for the percentage of patients with reduced kidney function among the defined groups of the cohort was calculated with the Clopper–Pearson method. The statistical analyses were performed with IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY, USA: IBM Corp.The study was approved by the regional ethics board in Umeå: EPN-Umeå, dnr: 2013/463-31M and amendment 2016/403-32. The study conformed to the provisions of the Declaration of Helsinki . The regional ethics board specifically decided that informed consent from the participants was to be considered redundant, especially due to the high mortality of MIBC as well as the retrospective nature of the study.The clinicopathological variables for each of the 220 analyzed patients were extracted from the extensive official database charting all MIBC patients who have undergone RC in Sweden and are presented in The findings regarding pathological renal values before the initiation of chemotherapy are presented in According to our findings, a considerable portion of the NAC-administrated patients who suffered a TEE during treatment had reduced renal function, as 41% (95% CI 23–61%) had one or more pathological values throughout the entire time period, up until the day of cystectomy. Fifty-four percent of the NAC-administrated patients who underwent their chemotherapy without a thrombolytic adverse event also had reduced kidney function, presenting a similar result as the TEE group. The most frequent pathological value amongst the NAC-treated TEE patients was P/S-creatinine, with nine patients (31%) showcasing a higher value than the established reference interval. This is possibly in accordance with P/S-creatinine being the most frequently used measurement for kidney function in Sweden. No noteworthy differences were found between the NAC-administrated subgroups regarding kidney function before the initiation of chemotherapy. Hence, the two groups of TEE patients and those who did not suffer a TEE could be considered to have the same baseline renal function before the first NAC cycle. The main objective of the study was to investigate renal function in NAC-administrated patients who had suffered a TEE and to assess their ability to potentially respond to LMWH-prophylaxis. Hence, the participants were divided into subgroups of those who did or did not develop thrombosis during the time between diagnosis and RC. NAC inherently contributes to an amplified TEE risk in MIBC patients undergoing RC, and recent findings have suggested that the choice of CVA for chemotherapy can influence the increased risk ,18,19. AAs the hypothetical LMWH treatment would be initiated at the start of chemotherapy (NAC), the distinction between the TEE and non-TEE patients would not be yet established. Therefore, there is relevance in also establishing the incidence of reduced renal function in NAC-administrated patients who have not suffered a TEE. In the NAC-administrated no-TEE group, 54% were found to have reduced renal function during the entire pre-RC period. Hence, this group showed similar results to the TEE-positive subgroup, indicating that LMWH could be subtherapeutic in the NAC-MIBC group as a whole. The NAC-eligible non-NAC group presented with a lower prevalence of pathological renal values than the groups (w/wo TEE) treated with NAC, possibly reflecting the negative effect that MIBC might inherently possess on kidney function. However, because of this study’s numerically limited cohort population, a larger patient selection is needed to further establish the incidence of reduced kidney function amongst NAC-administrated MIBC patients. Further important associated subjects to evaluate are how the current clinical use of LMWH contributes to reduced renal function, as well as extending the time period of analysis both pre-RC as well as post-RC. A strength of this study is that the analyzed measurements are meticulously extracted from individual medical records; thus, the presented findings could be regarded as highly reliable. Our findings show that a substantial portion of NAC-administered patients with TEEs had reduced renal function pre-RC, and therefore, they would potentially not be suited for renal clearance-dependent LMWH prophylaxis. However, further investigations are needed to fully comprehend the prevalence of reduced renal function amongst MIBC patients.


International research shows increased risks for SARS-CoV-2 infection and severe disease progression in people with migration history. In Germany, data on this topic is scarce. Aim of this contribution is to examine the association between migrant status and risk of SARS-CoV-2 infection and discuss potential explanatory mechanisms.We analysed data from the German COVID-19 Snapshot Monitoring online-survey and performed hierarchical multiple regression models to calculate probabilities for a self-reported SARS-CoV-2 infection. Main predictor variable was the migrant status; besides, the association with gender, age, education, household size, household language (German vs. other), and occupation in the health sector was analysed.Of 45,858 participants, 3.5% reported a current or previous infection with SARS-CoV-2, 16% reported own or parental history of migration. The probability of reporting an infection was 3.95 percentage points higher among migrants. The effect of different characteristics on self-reported SARS-CoV-2 infection varied. Higher probabilities were shown for individuals living in bigger households and those not speaking German at home. Stepwise integration decreased the observed association with migrant status. When adding an interaction term of migrant status and occupation in the health sector, the probability to report an infection was 11.5 percentage points higher for migrants working in the health sector.People with migration history, health sector employees and particular migrant health workers are at a higher risk of SARS-CoV-2 infection. However, the migrant status itself does not determine the risk of infection, but the living and working conditions. Therefore, targeted and multilingual prevention measures are needed that consider living and working conditions.• Higher SARS-CoV-2 infection risks are not solely determined by migrant status, but were shown for health care workers, people living in bigger households and those not speaking German at home.• As not the migrant status determines infection risks, multilingual and targeted prevention measures considering the living and working conditions of people are necessary.


In vitro data suggest the monoclonal antibody sotrovimab may have lost inhibitory capability against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. We aimed to provide real-life data on clinical outcomes in hospitalized patients. We retrospectively analyzed patients who were treated at the University Medical Center Hamburg-Eppendorf, Germany, between December 2021 and June 2022. Out of all 1,254 patients, 185 were treated with sotrovimab: 147 patients received sotrovimab monotherapy, and 38 received combination treatment with sotrovimab and remdesivir. We compared in-hospital mortality for the different treatment regimens for patients treated on regular wards and the intensive care unit separately and performed propensity score matching by age, sex, comorbidities, immunosuppression, and additional dexamethasone treatment to select patients who did not receive antiviral treatment for comparison. No difference in in-hospital mortality was observed between any of the treatment groups and the respective control groups. These findings underline that sotrovimab adds no clinical benefit for hospitalized patients with SARS-CoV-2 Omicron variant infections.IMPORTANCE This study shows that among hospitalized patients with SARS-CoV-2 Omicron variant infection at risk of disease progression, treatment with sotrovimab alone or in combination with remdesivir did not decrease in-hospital mortality. These real-world clinical findings in combination with previous in vitro data about lacking neutralizing activity of sotrovimab against SARS-CoV-2 Omicron variant do not support sotrovimab as a treatment option in these patients. As of September 2022, more than 6.4 million people have died from coronavirus disease 2019 (COVID-19) worldwide . Sotrovi3–n = 59] versus 85.1% [n = 74]; P = 0.012) and did not differ between the remaining treatment and control groups. Patients treated with sotrovimab as monotherapy on the regular ward less frequently received immunosuppressive therapy than the control group , but the rate of patients with immunosuppressive therapy did not differ between the other treatment and propensity score-matched control groups. Also, patients treated with sotrovimab as monotherapy in the ICU less frequently received chemotherapy than the control group . Among other subgroups, the rates of patients receiving chemotherapy did not differ between treatment and control groups. Among patients who were treated in a normal ward, rates of in-hospital mortality did not differ between treatment and control groups for those who were treated with sotrovimab , and for those who were treated with sotrovimab and remdesivir  , or in combination with remdesivir  and the respective control groups. In addition, we compared rates of in-hospital mortality for patients with Omicron BA.1, BA.2, or BA.4/5 sublineage infections for all subgroups and observed no significant differences (Table S1).During the study period, a total of 1,254 patients with SARS-CoV-2 Omicron variant infections were admitted and treated at the University Medical Center Hamburg-Eppendorf. Of those, 147 were treated with sotrovimab alone, and 38 received combination treatment with sotrovimab and remdesivir. After propensity score matching was performed, patients in the different treatment subgroups and the respective control groups did not differ in terms of sex, age, Charlson comorbidity index (CCI), treatment with dexamethasone, vaccination status, and history of coronary heart disease, chronic pulmonary disease, diabetes mellitus with and without end organ damage, and chronic kidney disease . The rate of patients with congestive heart failure was lower in the treatment group than in the control group for patients who received monotherapy with sotrovimab in the intensive care unit (ICU) group (67.8% [ = 0.72) . Likewisin vitro data have shown that sotrovimab appears to have retained activity against the Omicron BA.1 sublineage, but it has lost inhibitory capability against the BA.2, BA.4, and BA.5 sublineages . SARS-CoV-2 variant of concern (VOC) typing was part of the routine virological diagnostic, and samples were analyzed in an accredited diagnostic lab. VOC typing for the different linages was performed using several high-throughput TaqMan-based quantitative PCR (qPCR) panels based on detection of multiple mutations in the viral spike protein as previously published –18. Brie–This study was reviewed and approved by the Ethics Committee of the Medical Council of Hamburg (WF-052/20).All data generated or analyzed during this study are included in this article.


N = 417), approximately 17% had limited health literacy, and 22% reported experiencing difficulty accessing information about COVID-19. In adjusted analyses, respondents with limited health literacy ([adjusted odds ratio] aOR = 2.245) and Hispanic ethnicity (aOR = 2.149) had higher risk of reporting information access barriers. There was no association between language preference and reporting COVID-19 information barriers. However, individuals who are DHH with limited health literacy were at higher risk of experiencing information marginalization during the ongoing COVID-19 pandemic, highlighting the need for tailored information based on access needs. People who are deaf and hard-of-hearing (DHH) struggle with information marginalization and limited health literacy, challenging their ability to access information on preventing coronavirus disease 2019 (COVID-19). This study assessed the relationship between language preference, health literacy, and COVID-19 information barriers among parents who are DHH in the United States. Data were drawn from a larger study focused on individuals who are DHH who had given birth in the past 10 years. Respondents completed a web-based survey between March 2020 and July 2021. We segmented respondents by language preference  and used logistic regression models to test the hypothesis that language preference and health literacy were both associated with COVID-19 information marginalization. Of the total sample ( Over 49 million people in the United States (approximately 15%) are deaf and hard-of-hearing (DHH) . State aOne individual-level barrier to effective health communication with DHH people is inadequate health literacy. The DHH population faces widespread information marginalization and limited access to reliable information , creatinThere is limited research on the relationship between being DHH and experiencing negative consequences related to the COVID-19 pandemic. Early in the pandemic, DHH ASL users sought information about COVID-19 on the internet in English-based text forms . This inGiven the increased risk of COVID-19 infection among people who are DHH, the challenges of producing accessible health communication for this population, and overall lack of accessible COVID-related health information , the purData for this study were from the Survey on Pregnancy Experiences of Deaf and Hard-of-Hearing Women collected between May 2020 to July 2021. Participants were recruited through a convenience and purposive sampling strategy across the U.S. through social media, community-based and national organizations, independent living centers, and word-of-mouth. To participate, respondents needed to be DHH with hearing loss occurring before the birth of their most recent child, be age 21 years or older, and self-report birth of a child within the past 10 years. The study procedures were reviewed by the University of Michigan's Institutional Review Board. In total, 620 eligible respondents engaged in the survey.The survey included 80 questions related to respondents' own pregnancy experiences. English survey questions were adapted and translated into ASL and Spanish and placed on a web-based platform. The present study focused on questions related to COVID-19 information access, health literacy, and language preference. Survey covariates included age, racial identity, Hispanic ethnicity, and educational attainment.The primary outcome variable was measured using a single item, “Have you had trouble getting important and easy access to information about the coronavirus?” Respondents who answered affirmatively were additionally asked, “What challenges getting information about coronavirus have you had?” and were permitted to select multiple closed-ended choices and/or provide free-text, open-ended responses.very confident, confident, neutral, somewhat confident, or not confident. Those indicating being very confident or confident were coded as having adequate health literacy—all other respondents were coded as having inadequate health literacy.Health literacy was measured using a single item, “How confident are you filling out medical forms by yourself?” developed by Chew et al. . This itn = 4), this group was removed from the analysis.Language preference was identified by asking, “What language(s) do you prefer to use? Please select all that apply”: (1) sign language or ASL, (2) English, (3) Spanish, or (4) Other (open-ended response). Language preference was recoded into mutually exclusive categories. Specifically, we coded respondents who preferred (1) ASL only, (2) ASL or English, (3) English only, or (4) any other spoken language. Due to the small sample size of the other spoken language group . Among the 417 respondents who responded to the health literacy and COVID-19 questions, approximately 17% of the sample were identified as having inadequate health literacy, and 22% reported experiencing difficulty accessing information about COVID-19. In bivariate analyses, inadequate health literacy , but not language preference , was associated with COVID-19 information barriers. In un-adjusted models, older respondents, those with lower educational attainment, of Hispanic ethnicity, and those with inadequate health literacy had higher ORs of reporting experiencing COVID-19 information barriers (Table 2). When adjusting for covariates, respondents with lower educational attainment, inadequate health literacy, and Hispanic ethnicity had higher risk of experiencing information access barriers .The analytic sample was predominantly White (89%) and college-educated  provided open-ended responses describing barriers to retrieving information from public broadcasts about COVID-19, obtaining information about testing and vaccinations, and finding reliable and accessible sources of information.Here is one response: “I can't find reliable sources [on] the internet. The few I find don't really do a good job of explaining coronavirus to the general public. Almost none of the news sources have reliable, high-quality captioning.”Finding reliable sources was an issue due to the conflicting information and “click bait” on the internet. In addition, respondents reported a lack of accurate captioning on news stations and issues with ASL interpreters being cut out of the video frame on public emergency broadcasts. An additional barrier was the pace sources at which released new information, with participants reporting that “information [was] conflicting” and that it felt “overwhelming [because of the] changing information every day or every week.”Although recent research has focused on DHH ASL-users' information seeking behavior with COVID-19 , little Due to the larger study's focus, the sample is limited to DHH parents who had given birth in the past 10 years. Due to the sampling design , these results may not be generalizable to the population of DHH ASL-users and spoken-language users in the U.S. In addition, the outcome variable and health literacy screening items were single-item measures. Future research should use measurement tools with a broader definition of health literacy and gain further information on specific access barriers related to COVID-19 . Lastly, due to small cell sizes, we could not test interaction models. Future research should assess the moderating effects of predisposing and enabling factors on information access outcomes.People who are DHH with inadequate health literacy are at higher risk of experiencing information marginalization during the ongoing COVID-19 pandemic. Given existing, well-known barriers to individuals' with DHH information access during emergencies, these results further highlight the need for emergency information and health communications to be tailored for accessibility and information needs.


It was confirmed at the survival analysis  and at the multivariable analyses . A higher candida score seemed to increase the hazard for candidemia occurrence , while vasopressor therapy was negatively associated with the outcome . Conclusions: This study confirms that the incidence of candidemia was significantly higher in critically ill COVID-19 patients supported with VV-ECMO than in critically ill COVID patients who did not meet criteria for VV-ECMO.Background: The incidence of candidemia in severe COVID-19 patients (0.8–14%) is two- to ten-fold higher than in non-COVID-19 patients. Methods: This retrospective analysis aimed to analyse the incidence of bloodstream infections (BSI) due to Candida in a cohort of COVID-19 patients supported with ECMO. Results: Among 138 intubated and ventilated patients hospitalized for ≥10 days in the intensive care unit of a teaching hospital, 45 (32.6%) patients received ECMO support, while 93 patients (67.4%) did not meet ECMO criteria and were considered the control group. In the ECMO group, 16 episodes of candidaemia were observed, while only 13 in patients of the control group (36.0% vs. 14.0%,  Candida immune response have been investigated ) for continuous variables. Differences in categorical data were compared using the chi-square test or Fisher’s exact test, as appropriate. For continuous normally distributed two-group data, we compared differences using Student’s he model . AdjustiThe Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed to create the study. The Ethics Committee of Policlinico Umberto I approved the study with number 109/2020.p-value < 0.001). The median length of ECMO support for the 45 patients was of 18 days (IQR 12–23). Regarding the anamnestic characteristics and clinical severity at hospital admission, patients with ECMO support did not show statistically significant differences compared to unsupported ones, with the exception of age , SAPS II score , hypertension  hepatopathy , vasopressor therapy , inotropes therapy , bacterial colonization , and BSI . Finally, there was no statistically significant difference in mortality between the ECMO supported patients and unsupported ones   received ECMO support, while 93 patients (67.4%) suffering from severe hypoxemic acute respiratory failure did not meet ECMO criteria and were considered the control group. Overall, the median length of stay was 20 days (IQR 14–30), but patients with ECMO support had longer hospitalization than patients without support  .p-value 0.004), and there were no differences in the Candida species involved  . This fiThe analysis of predictors associated with candidemia stratified by ECMO support showed that only the candida score had an impact on the odds of Candidemia occurrence in patients who needed ECMO support . ECMO unsupported patients were influenced by the candida score, although to a lesser extent , and by having been affected by at least one previous non-candidemic BSI  .p-value 0.004). Previous data on invasive candidiasis among severe COVID-19 patients ranged between 0.8 and 14% with an increased rate of candidemia, especially in comparison to the historical non-COVID-19 cohort [Candida species requires a period of 7–10 days for the development of IC after exposure to the risk factors [In this retrospective study, the incidence of candidemia was significantly higher in critically ill COVID-19 patients supported with VV-ECMO than in critically ill COVID patients who did not meet criteria for VV-ECMO  [Candida overgrowth in SARSCoV2 infected patients [Candida infections in critically ill COVID-19 patients was suggested by the observation of impaired immune response to those pathogens characterized by the abrogated release of IL-6, TNF, IL-1α, and IL-1β toward Candida albicans [Physiologically, the fungal microbiome can act as a reservoir for commensal fungi such as iseases) . In partpatients ,29. Morepatients ,31. Intepatients ,33. Finapatients . Particualbicans . Candida species despite the fact that C. albicans remains the most common cause of Candidemia observed among the COVID-19 patients [C. parapsilosis than to C. albicans and C. tropicalis, with no difference between ECMO supported and unsupported patients. Probably, the increased incidence of C. parapsilosis  was linked with the specific characteristic of our cohort composed by critically ill patients with severe COVID-19 prognosis and heavily treated with the high invasive ICU procedures and/or ECMO  [Regarding the etiology, a recent review of the studies on the topic showed an upsurge in the cases due to non-albicans patients . In our terials) . The analysis of predictors associated with candidemia in our study showed that only the candida score had an impact on the odds of Candidemia occurrence in patients who needed ECMO support . On the other hand, the candida score  and a previous episode of non-candidemic BSI  were predictors associated with candidemia in ECMO unsupported patients. Interestingly, the candida score ranged between 1 and 4 in patients with candidemia enrolled in our study. The observation indicates that this scoring tool, while remaining a good predictor of candidemia, tends to underestimate the risk in the setting of severe COVID-19. In fact, invasive candidiasis is considered highly improbable in subjects with candida score < 3, and rates of invasive candidiasis are estimated at 0% in patients with score = 2 or 3, and 17.6% in patients with score = 4 in ICU patients . MoreoveThe use of ECMO assistance was found related with the risk of candidemia in this study: in particular, the potential risk is linked to the long duration of ECMO support which can lead to intestinal ischemic complications and thus favor microbial translocation . About tTo the best of our knowledge, this is the first study focused on the incidence of fungal infection in critically ill COVID-19 patients undergoing ECMO support. It is of paramount importance to highlight the possible risk factors in this special population. However, this study has several limitations: first, it is a retrospective study, but the control group has been powered using a propensity score technique, a prospective study should be designed to better assess the impact of different risk factors. The use of renal replacement therapy is also associated with the occurrence of candidemia, but we could not investigate this potential risk factor in the propensity score model because only a few patients in both groups were treated with this technique . Second,In this retrospective cohort study, the incidence of candidemia was significantly higher in critically ill COVID-19 patients supported by VV-ECMO than in non ECMO patients caused by the impaired immune response. Further studies are needed to better understand the risk factors and mechanisms underlying this marked incidence.


Retraction Note: Mol Cancer 18, 25 (2019)https://doi.org/10.1186/s12943-019-0958-6The Editor-in-Chief has retracted this article at the authors' request. After publications, concerns were raised regarding image overlap in Figs. 4 and 5, which the authors addressed via a Correction . HoweverFurthermore, BGC823, MGC803 and SGC7901 cells used in this study are known to be contaminated  with HeLa cells, making them an unsuitable model for gastric cancer [The authors have provided the raw data to address the image concerns, but have requested to retract the article due to the cell line contamination.Shuli Zhao, Weiwei Tang and Hongyong Cao agree to this retraction. Chen Lu and Kai Fu have not responded to any correspondence from the editor or publisher about this retraction. The Publisher has not been able to obtain current email addresses for Dawei Rong and Betty Zhang.