This study investigated the associations between COVID-19 related stigma and post-traumatic stress symptoms (PTSS); and the associations between PTSS and COVID-19 related stigma, HIV status, COVID-19 status and key HIV population status.This was a secondary analysis of data of 12,355 study participants generated through an online survey that recruited adults from 152 countries between July and December 2020. The dependent variables were COVID-19-related stigma and PTSS. The independent variables were HIV status (positive/negative), transaction sex (yes/no), use of psychoactive drugs (yes/no), and vulnerability status . The confounding variables were age, sex at birth , level of education, sexual minority individuals (yes/no) and country income level. Multivariable logistic regression analyses were conducted to determine associations between the dependent and independent variables after adjusting for confounders.There were 835 (6.8%) participants who experienced COVID-19 related stigma during the pandemic and 3,824 (31.0%) participants reported PTSS. Respondents who were living with HIV , tested positive for COVID-19 , engaged in transactional sex  and used psychoactive drugs  had significantly higher odds of experiencing COVID-19 related stigma. Individuals with vulnerability status  and who experienced COVID-19 related stigma  had significantly higher odds of PTSS.Individuals with vulnerability status may be at increased risk for COVID-19 related stigma. Key and vulnerable populations who were living with HIV and who experienced stigma may be at a higher risk of experiencing PTSS. Populations at risk for PTSS should be routinely screened and provided adequate support when they contract COVID-19 to reduce the risk for poor mental health during COVID-19 outbreaks and during future health crisis with similar magnitude as the COVID-19 pandemic. Many individuals and their families who recovered from COVID-19 have faced double challenges- the physical health fallout from experiencing COVID-19 symptoms and related complications, and the COVID-19 related stigma that is driven by fear and misconception about the disease . Stigma One of the potential consequences to experiencing stigma is depression , 8. DeprThere are many individuals who may feel more vulnerable to the consequences of COVID-19 associated stigma. People living with HIV, sexual minority individuals and key populations in the HIV response  face stIn the present study, we utilized the Framework Integrating Normative Influences on Stigma (FINIS) as the conceptual model to facilitate understanding stigma experiences . The fraThe Framework recognises that both social and illness characteristics shape the experience of stigma. Additionally, social and illness characteristics combined to shape the experience of stigma, and different levels of social life influence the experience of stigma . We postIn addition, though people living with HIV, sexual minority individuals and key populations have a comparable biological risk profile for COVID-19 to that of the general population –43, theiThe aims of this study, therefore, were to assess associations between reported experience of COVID-19 pandemic related stigma and living with HIV and key HIV population status; and assess the association between post-traumatic stress symptoms and the self-reported experience of COVID-19 pandemic stigma. We hypothesised that (1) people living with HIV and being a member of a key population will be positively associated with the experience of COVID-19 stigma and (2) the experience of COVID-19 stigma will be positively associated with post-traumatic stress disorder.Ethical approval was obtained from the Human Research Ethics Committee at the Institute of Public Health of the Obafemi Awolowo University Ile-Ife, Nigeria (HREC No: IPHOAU/12/1557). Ethical approval was also obtained from Brazil (CAAE N° 38423820.2.0000.0010), India (D-1791-uz and D-1790-uz), Saudi Arabia (CODJU-2006 F) and the United Kingdom  for the conduct of the primary study. Study participants checked a box to indicate consent before participating in the online survey.This was a secondary analysis of data generated through a cross-sectional international study that recruited adults from 152 countries through an online survey between July and December 2020 during the first wave of the COVID-19 pandemic. Study participation was open to anyone 18 years and older. There were no exclusion criteria.The sample size for the primary study was calculated based on the highest global prevalence of a mental health disorder in 2019. The pre-survey minimum sample size for this study was set at 59 valid respondents from each of the 193 member States of the United Nations based on the estimated prevalence of the most common global mental health disorder in 2019, (3.94% for anxiety disorder) ; a desirwww.mehewe.org) were asked to share the survey link with their contacts around the world to facilitate recruitment. The survey link was also posted on social media groups , network email lists and WhatsApp groups. The details of how the survey was conducted and the data collection tools are published elsewhere [Study participants were recruited through respondent-driven sampling. Initially, 45 members of the mental health and wellness (MEHEWE) study group . For COPost-traumatic stress symptoms (PTSS) were measured using the 17-item self-report PTSD checklist for civilians . This isThe independent variables were the subpopulations previously identified. These are: HIV key populations  vulnerable to social stigma , 60, peoThe confounding variables were age at last birthday, sex at birth , sexual identity , level of education  and country of resident’s income level (low-income countries (LICs), lower middle-income countries (LMICs), upper middle-income countries (UMICs) and high-income countries (HICs). Respondents had to pick a country of residence from a list. The country was them categorised into the country income level using the 2019 World Bank Data on country classification by Gross National Income .Raw data were downloaded, cleaned, and imported to SPSS version 23.0  for analysis. A multivariable logistic regression analysis was conducted to determine the associations between reported experience of COVID-19 related stigma and the independent variables  after adjusting for confounders. A second multivariable logistic regression analysis was conducted to determine the associations between PTSS and the independent variables  after adjusting for confounders. Adjusted odds ratios (AOR), 95% confidence intervals (CI), and p values were calculated. Statistical significance was set at 0.05.Of the 12,355 respondents whose data were extracted for this study, 835 (6.8%) experienced COVID-19 related stigma. Table Table The study findings suggest that populations from groups that have traditionally experienced stigma and discrimination  were more likely to experience COVID-19 related stigma. Also, people who experienced COVID-19 related stigma were more likely to report PTSS than those who did not. Individuals who were vulnerable to social stigma had higher risks of PTSS. Thus, the findings suggest that groups of people who were already at risk of experiencing stigma may be more vulnerable to experiencing COVID-19 related stigma and the challenges that come with this addition stigma such as PTSS. The results of this study support the study hypotheses.This is one of few studies to provide empirical evidence on the possible risks for experiencing COVID-19 related stigma, and the effects of this on the mental health of affected individuals. Stigma can affect individual’s mental health negatively; and marginalized groups, including sexual minority individuals, individuals with physical diseases and socially excluded individuals, have a higher risk of experiencing stigma , 65.The study has some limitations. This was a cross-sectional study which makes it difficult to establish a cause-effect relationship between the variables. Also, a non-probability sampling technique was used to recruit the study population. While this is the most appropriate way to recruit hidden populations like those identified for this study –68, and First, the study findings showed that populations that more likely to experience stigma and discrimination were also more likely to experience COVID-19 related stigma. Membership in stigmatised groups is known to amplify the risk of the stigma associated with health problems . This isThe study findings also suggest that experiencing COVID-19 related stigma and discrimination may increase the risk of PTSS. This risk is about five times greater for people living with HIV and those who tested positive for COVID-19. Thus, being infected with COVID-19 exposes key populations living with HIV to the risk of a third stigma. Our finding agrees with previous research showing that stigma is a risk factor for post-traumatic stress disorder , 79. In It is recognised that COVID-19 stigma results from a complex web of expectations caused by individual and contextual interactions between the stigmatised and the stigmatisers. The theoretical framework that drives this study (FINIS) attempts to explain the community and individual factors that drives stigma. It recognises that the risk of stigma is higher when persons who hold devalued statuses are aware of this devalued social identity as this influences the perception and response to the social slights of stigma and acts of discrimination . Key popFurthermore, we observed that individuals who do not disclose their sexual identity seem to be protected from COVID-19 related stigma. Though we handled sexual identity as a confounding variable, the study finding suggests that this variable may moderate the reporting of stigma. Prior studies identified that sexual minority individuals avoid disclosing their sexual identity in real life to reduce being stigmatized –85. The Our study confounding variables - age, educational status, sex at birth and the country of residence - may also moderate the experience of stigma and PTSS. We observed that the likelihood of experience COVID-19 related stigma and PTSS decreased with age, as reported in previous studies –89. The In conclusion, populations at risk of experiencing stigma prior to the pandemic such as people who inject drugs, transactional sex workers, sexual minority individuals and people living with HIV, were at higher risk of experiencing COVID-19 related stigma. The risk of PTSS may be higher for people who face COVID-19 related stigmatization and those with combined HIV and COVID-19 infection. People living with HIV, key populations and sexual minority individuals may need to be screened for PTSD when accessing health care services to facilitate prompt management. The study suggests a complex relationship with clustering of various stigmas that may have been deepened by the COVID-19 pandemic.


Immune checkpoint inhibitors (ICIs) have been investigated in epithelial ovarian cancer in first-line and recurrent settings. When used as a single agent or in combination with chemotherapy, they have largely failed to improve patients’ outcome and thus, have not entered routine use in clinical practice. However, there are signs of promising activity in some early and late-phase clinical trials, combining immune checkpoint inhibitors with effective targeted agents, such as those targeting the tumor blood supply (antiangiogenics) or when taking advantage of impaired intra-cellular machinery that are unable to repair major cell damage (for example with poly-ADP-ribose inhibitors (PARP)). Further research is still needed to define predictive biomarkers that can identify patients more likely to respond to ICI combinations. New targets and treatment strategies are under investigation to define if and how immunotherapy can be incorporated into the treatment of epithelial ovarian cancer.A deep understanding of the tumor microenvironment and the recognition of tumor-infiltrating lymphocytes as a prognostic factor have resulted in major milestones in immunotherapy that have led to therapeutic advances in treating many cancers. Yet, the translation of this knowledge to clinical success for ovarian cancer remains a challenge. The efficacy of immune checkpoint inhibitors as single agents or combined with chemotherapy has been unsatisfactory, leading to the exploration of alternative combination strategies with targeted agents and angiogenesis inhibitors) and novel immunotherapy approaches. Among the different histological subtypes, clear cell ovarian cancer has shown a higher sensitivity to immunotherapy. A deeper understanding of the mechanism of immune resistance within the context of ovarian cancer and the identification of predictive biomarkers remain central discovery benchmarks to be realized. This will be critical to successfully define the precision use of immune checkpoint inhibitors for the treatment of ovarian cancer. Ovarian cancer represents the leading cause of death due to gynecological malignancies in developed countries, and about 19,710 new cases are estimated in the United States in 2023 ,5. NeverImmune therapy and particularly immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are now incorporated in the management of many solid tumors, including endometrial, cervical, melanoma, lung, head and neck, kidney and urothelial cancers, triple negative breast cancer and microsatellite unstable tumors ,9,10,11.The tumor microenvironment (TME) plays a pivotal role in sustaining cancer cell proliferation, invasion and metastatic spread and influences anti-cancer treatment sensitivity or resistance . Moreove+ T-cells and CD8+/regulatory T-cells (Treg) ratio and survival in EOC [BRCA1 mutation, but not BRCA2, was associated with a higher level of CD8+ TILs [Ovarian cancer is a recognized immunogenic tumor, and the presence of T cells within the epithelial component of the tumor (tumor-infiltrating lymphocytes—TILs) has an established prognostic role. Zhang et al. demonstrated an improved progression-free survival (PFS) and overall survival (OS), following debulking surgery and adjuvant chemotherapy in patients whose tumors were characterized by the presence of TILs, defined as CD3+ cells . In the l in EOC . CD8+ TIl in EOC . BRCA1 mD8+ TILs . As expeD8+ TILs . Recent D8+ TILs . Other iD8+ TILs ,22,23.Inhibition of the cytotoxic T-cell response is one of the main mechanisms used by cancer cells to evade the immune system and is mediated by several factors, such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the programmed death receptor 1 (PD-1) and its ligand PD-L1, whose inhibition with ICIs constitutes one of the recent revolutions in cancer treatment ,25. The Anti-PD-1/PD-L1 agents have been investigated for the treatment of EOC in different settings, such as first-line, platinum-sensitive or platinum-resistant recurrence, and strategies explored thus far have included single-agent or combination treatment or maintenance approaches . The mosImmune checkpoint inhibitors have been investigated as single agents in the recurrent setting with limited signs of activity and without biomarkers of response identified . The actAlthough PD-L1 in EOC is known to be associated with a poor prognosis and suppression of CD8+ T-cell , the lacGiven the complexity of the mechanism of immune evasion adopted by cancer cells, a simultaneous inhibition of different pathways relevant for tumor cell proliferation and progression may represent a successful approach to increase treatment performance. Thus, as performed in many other cancer types, ICIs have been added to the different available standard or investigational agents to examine their activity in the setting of newly diagnosed or recurrent EOC .Chemotherapy remains the cornerstone of treatment for EOC in first-line and in the recurrent settings. Different preclinical and clinical findings have supported the rationale of combining chemotherapy with immunotherapy agents to enhance antitumor activity . When caMYC amplification was reported to induce an immunosuppressive microenvironment sustained by an increased expression of PD-L1 [MYC amplification [Preclinical data showed that doxorubicin promotes antigen presentation and increases T-cell infiltration, representing a promising partner for immunotherapy combinations . In platof PD-L1 , and prefication .Two phase 3 studies combining avelumab with chemotherapy did not met the primary endpoint of improving median progression free survival in either the recurrent or first-line setting ,42. The In the neoadjuvant setting, pembrolizumab has been investigated in combination with carboplatin and paclitaxel for four cycles, followed by interval debulking surgery and standard adjuvant treatment (+/− bevacizumab) with or without pembrolizumab up to 2 years in a phase 2 randomized trial, and the results have been presented at the 2021 American Society of Medical Oncology (ASCO) conference . The addThus, as of today, the available data do not support the addition of ICIs to standard chemotherapy in EOC, and other treatment strategies have been explored to define if a role for ICIs in EOC might still be foreseen.The presence of crosstalk between immune and endothelial cells within the TME has underscored the rationale to combine ICIs and antiangiogenic agents in different disease settings ,67,68,69BRCA mutation or HRD tumors, might have a more favorable outcome with the addition of ICIs to standard treatment.Following the positive results reported from several phase 3 trials in first-line and recurrent settings, the anti-VEGF agent bevacizumab has been incorporated into the standard of care armamentarium for the treatment of EOC ,76,77,78More recently, the results of the phase 3 ATALANTE trial, which investigated the combination of atezolizumab, bevacizumab and platinum-based chemotherapy in a platinum-sensitive recurrent setting, have been presented. As observed with other similar combinations, this trial also did not meet its primary endpoint and no PFS benefit was observed, regardless of PD-L1 expression .The antiangiogenic multikinase inhibitor lenvatinib has been combined with pembrolizumab in an ongoing phase 2 basket study (NCT03797326), including a cohort of patients with recurrent OC, where an intriguing ORR of 32.3% was observed when used as the fourth line of treatment . The stuBRCA mutation or HRD, this results in cell death according to the well-described mechanism of synthetic lethality [PARPis represent one of the major paradigm shifts in the treatment of EOC in first-line and recurrent settings and are now part of the standard of care . The maiethality . In addiethality ,81. Precethality . TogetheBRCA-mutated or wild-type tumors or according to HRD status [BRCA wild-type tumor is limited [BRCA wild-type and in the non-HRD population (ORR 19% in both) might underscore the synergistic effect of these two agents in this difficult-to-treat population [The combination of niraparib and pembrolizumab showed a limited efficacy in a small phase 1/2 trial (TOPACIO) in a heterogenous population of patients with recurrent platinum-resistant or platinum-ineligible EOC . The repD status . However limited ,84 as th limited ,36. Thuspulation .BRCA 1/2 mutated platinum-sensitive recurrent EOC, olaparib combined to durvalumab provided an ORR of 71.9% with a median duration of response of 10.2 months, which was better than when this combination was offered as second-line treatment [BRCA 1/2 wild-type tumors, the ORR was 34.4% with a median duration of response of 6.9 months [In patients with germline reatment . In pati9 months . Despite9 months .BRCA-mutated and BRCA wild-type PARPi naïve patients with platinum-sensitive recurrent EOC [BRCA wild type were initially presented at the 2020 European Society for Medical Oncology (ESMO) conference [® next-generation sequencing (NGS) on tumor tissue. The GIS was defined as positive if the loss of heterozygosity (LOH) score was ≥14 and a mutation in BRCA 1/2 or in another DNA repair genes  were present. No difference was observed among GIS positive and GIS negative patients; the combination of durvalumab and olaparib induced a similar ORR in BRCA-mutated patients but a lower ORR (50%) in GIS positive in the same setting [BRCA-mutated subjects is also much required.Multimodality combinations assessing PARPis, antiangiogenics and ICIs administered simultaneously are feasible given the non-overlapping toxicity profile of these agents. The phase 2 MEDIOLA trial investigated double and triple combinations in rent EOC ,52. The BRCA or other homologous recombination repair genes mutations [Another triple combination with dostarlimab, bevacizumab and niraparib showed interesting signs of activity with an ORR of 17.9% in a small cohort of patients with platinum-resistant OC . No diffutations .Ongoing clinical trials are now investigating the role of the triplet combination of PARPis, antiangiogenic and ICIs in first-line maintenance setting. This multimodality strategy is of particular interest for HRD negative tumors, that are usually less sensitive to PARPis. Recently, positive results in PFS at an interim analysis of the DUO-O trial (NCT03737643), investigating durvalumab plus olaparib added to platinum-based chemotherapy and bevacizumab, have been announced . AdditioThe combination of anti-PD-1/PD-L1 with anti-CTL-4 is another effective strategy that has been pursued with positive results in different solid tumors, showing an increased efficacy with a dual checkpoints inhibition ,27,87,88The combination of nivolumab and the anti-CTL-4 tremelimumab, as sequential versus concomitant administration, in platinum-resistant heavily pretreated patients with HGSOC, did not show signs of activity, having reported no objective response and limited PFS .A small phase 2 study presented at the 2021 Annual Meeting of the Society of Gynecology Oncology (SGO) investigated the combination of durvalumab and the anti-CTL-4 tremelimumab in combination with neoadjuvant chemotherapy. All 23 enrolled patients achieved an objective response with a complete resection to no residual disease at the interval debulking surgery in almost 74% of the patients . The neoClear cell ovarian cancer (CCOC) is a rare histological subtype, with a variable incidence according the geographic areas and ethnicity . If compMicrosatellite instability (MSI) is a well-known predictive biomarker of response to ICIs regardless of tumor type and, as a result, pembrolizumab has received a histology-agnostic approval for MSI-high tumors . While MA randomized multicenter phase II trial is ongoing to investigate the efficacy and safety of durvalumab versus physician-choice chemotherapy in patients with recurrent clear cell ovarian cancer (NCT03405454) and may provide better evidence of the role of anti-PD-1/PD-L1 in this specific histological subtype .Different biomarkers predictive of ICI efficacy or resistance have been explored in many tumor types with the aim of better selecting those patients that could most benefit from these agents and spare exposure to unnecessary toxicity in patients who would not have a predicted improvement in tumor response or survival. Many elements drive responses to ICIs, such as the tumor microenvironment milieu, the tumor genetic signature, the host immune system and environmental factors .PD-L1 expression on either tumor cells or tumor-infiltrating immune cells has emerged as one of the first biomarkers undergoing investigation. Regulatory approval for the use of ICIs is limited to a specific threshold of PD-L1 expression in some tumor types  . HoweverIn EOC, randomized phase 3 trials to date have not demonstrated a benefit with the addition of an ICI to standard treatment ,49,103. Genomic aberrations continue to emerge as potential predictive biomarkers for targeted treatment and immune therapy. Microsatellite instability is a well-established biomarker of response to ICIs and pembrolizumab has been granted approval in patients with germline or sporadic genomic aberrations in mismatched repair genes ,104. ThiWhilst the role of the tumor microenvironment or genomic features in influencing the activity of ICIs remains to be well-identified, there is increasing research to investigate the role of gene expression signatures in tumor or in tumor-infiltrating immune cells. These may in future provide a better insight into those features that correlate with response to immunotherapy.Over the last decade, immunotherapy and particularly ICIs, have improved outcome in many cancers. Practice changing clinical trials have shown an improvement in patients’ outcome when anti-PD-1/PD-L1 have been used as a single agent or in combination with chemo or targeted therapy in different malignancies and have become the standard of care in many settings ,28,29,67BRCA-mutated tumors? Why do most patients with EOC not respond to ICI treatment? Many similar questions remain unanswered and there is an urgent unmet need to understand the biological mechanisms that sustain this resistance. Deep translational analysis on tumor tissue and liquid biopsy collected before and during an ICI-based treatment are of utmost importance to investigate the tumor microenvironment and its changes, following exposure to treatment, as well as postulating potential predictive biomarkers of activity or defining the mechanism of intrinsic resistance [It has also to be recognized that in single-agent and combination clinical trials, some patients responded to an ICI-based treatment with reports of single cases of long-lasting clinical benefit and ‘exceptional’ responders; however, it is evident that many questions remain ,36,99. Wsistance ,110. Parsistance .Another relevant aspect for discussion is in identifying which is the most reliable endpoint to be used in clinical trials assessing the ICI efficacy. In phase 2 trials, ORR is typically used as a primary endpoint, but it is still uncertain if this is the best surrogate for ICI efficacy, given that the pattern of response to ICIs differs from the one commonly observed with chemotherapy or target agents ,113. MorFurthermore, we still need to identify which immunotherapy agents beyond ICIs warrant investigation in EOC, and the drug development field is actively exploring new opportunities. Tumor vaccines , adoptivUpon the identification of promising agents, a personalized approach selecting the best immune-oncology drug tailored to the patient’s immune milieu at a specific time-point could be an ideal and promising strategy to target the cancer-specific immune evasion. This will require a real-time conduct of clinical and translational research in parallel to fast-track knowledge from the bench to the bedside to improve the outcome of women diagnosed with advanced EOC.Improving immunotherapeutic approaches for ovarian cancer is an urgent priority. Initial studies were relatively disappointing, and these have led to a careful evaluation of the impact of the tumor microenvironment in modulating immune responses and the careful assessment of combination strategies. These seem to be demonstrating benefits, and very early signals from some studies have suggested improvement in progression-free survival in the first-line setting.The importance of patient selection, personalized treatment and the identification of the optimal target and the best combination regimen are of utmost importance in furthering the development of immunotherapy in EOC. Collaborative initiatives for translational and clinical trials are strongly needed to expedite progress in this field and ultimately improve the care of women with ovarian cancer.


Background: Previous studies in Dutch young adults revealed that individuals with self-reported impaired wound healing reported poorer mood, increased inattention and impulsivity, poorer quality of life, and poorer immune fitness compared to healthy controls. Another study revealed that the negative impact of lockdowns during the 2019 coronavirus disease (COVID-19) pandemic was significantly more profound among the impaired wound healing group than the control group. The purpose of the current study was to replicate and extend these findings among young adults living in Germany. Methods: A retrospective, cross-sectional survey was conducted among N = 317 young adults living in Germany, 18–35 years old. They were allocated to the IWH group (N = 66) or the control group (N-251). Participants completed the Attention Control Scale, and mood, quality of life, and immune fitness were assessed with single-item ratings. All assessments were made for (1) the period before the COVID-19 pandemic, (2) the first lockdown period, March–May 2020, (3) the first no-lockdown period, summer 2020, (4) the second lockdown, November 2020 to May 2021, and (5) the second no-lockdown period, summer 2021. Results: The impaired wound healing group reported significantly poorer mood, quality of life, and immune fitness. The effects were evident before the pandemic. The impaired wound healing group scored significantly poorer on attention focusing, but no significant differences between the groups were found for attention shifting. During the pandemic, negative lockdown effects  were evident in both groups but significantly more profound in the impaired wound healing group. No differences between the groups were found for the no-lockdown periods. Conclusion: Individuals with self-reported impaired wound healing have significantly poorer mood, attention focusing, and immune fitness and report a poorer quality of life than healthy controls. The impact of COVID-19 lockdowns was significantly more profound in the impaired wound-healing group. The lockdown periods during the 2019 coronavirus disease (COVID-19) pandemic had substantial negative socioeconomic consequences [Although data showed that the impact of lockdowns is highly heterogeneous, depending on the sample under investigation, for individuals who struggled to cope with lockdown restrictions, these periods have been associated with poorer mood  ,4,5,6. AIn Germany, several actions were taken to limit the spread of the SARS-CoV-2 virus, described in detail elsewhere . In MarcThe COVID-19 restrictions also limited the care of wound patients ,11. OutpThe aim of the current study was to evaluate the impact of COVID-19 and associated lockdowns on the mood, quality of life, and immune fitness of German young adults with self-reported impaired wound healing. Research conducted before the pandemic among the same age group in The Netherlands revealed that, compared to healthy controls, young adults with self-reported impaired wound healing reported poorer mood , poorer An online survey was conducted among German young adults from 18 to 35 years old. Participants were recruited via email and printed flyers. The survey was administered via the online platform LimeSurvey  and could be completed in German or English language. Participants could enter a prize draw to win one of four 25 Euro Amazon gift cards. The study was conducted between mid-November 2021 and the end of March 2022, and informed consent was obtained from all participants. Ethics approval was obtained from the Ethics Committee of the Medical Faculty of TU Dresden . A detailed description of the study methodology and the dataset are published elsewhere .Participants indicated whether or not they had experienced slow-healing wounds and/or wound infections during the past year. Based on their answer, they were allocated to (1) a control group that answered ‘no’ to both questions and (2) an IWH group that reported experiencing wound infection and/or slow-healing wounds.Demographic data were collected, including age and sex. Attention control was assessed with the 20-item Attention Control Scale (ATTS) . Items hp < 0.0125. Comparisons between the IWH and control group were conducted with the Independent-Samples Mann-Whitney U Test. Percentual data were compared with the N-1 Chi-squared test. Differences between the groups were considered statistically significant if p < 0.05.Statistical analyses were conducted with SPSS . Within-subject comparisons of the mood assessments of the four time points were conducted with the Related-Samples Friedman’s Two-Way Analysis of Variance by Ranks test. Bonferroni’s correction was applied, and differences were considered significant if A total of n = 317 individuals participated in the study. Of them, n = 66 were allocated to the IWH group, and n = 251 to the control group. Their demographic data are summarized in The control group comprised significantly more women than the IWH group. The IWH group reported a significantly lower perceived immune fitness and significantly more individuals of this group had reduced immune fitness. In addition, the IWH group reported a significantly lower quality of life than the control group. The difference in sleep quality between the groups was not statistically significant.Results on attention control are summarized in The mood and quality of life outcomes are summarized in The mood effects were more pronounced in the second lockdown than in the first lockdown. During the two no-lockdown periods, mood and quality of life did not differ from before the COVID-19 pandemic, except for stress (which was significantly lower during the first no-lockdown period) and optimism (which was significantly lower during the second no-lockdown period).Data on immune fitness is summarized in This study in young adults in Germany confirmed that mood, quality of life, and immune fitness are poorer among individuals with self-reported impaired wound healing compared to healthy controls. It extended previous knowledge on the possible impact of attentional deficits  by showiThe current study did not investigate the causes of the observed differences in lockdown effects on mood, quality of life, and immune fitness between the group with and without self-reported impaired wound healing. It could be speculated that intermittent or poor wound treatment due to postponed care during the pandemic may be responsible for the differences. Alternatively, it may be in circumstances of psychological distress (such as a lockdown) that this may have a greater impact on individuals with impaired wound healing compared to healthy controls. Previous research in support of this hypothesis found that individuals with self-reported impaired wound healing reported significantly lower levels of mental resilience than healthy controls . In addiLimitations of this study include the fact that the data were self-reported and assessed retrospectively. Therefore, recall bias may have had an impact on the participants’ responses. Second, the classification of the participants into the impaired wound healing group versus the control group was based on self-reported data, but given the nature of the study design (an anonymous survey), this could not be verified by a formal diagnosis. Future studies should preferably be conducted in formally diagnosed patients . Third, the study comprised a relatively small convenience sample of young adults (18 to 35 years old) living in Germany. Therefore, it is unclear to what extent our findings can be generalized to other age groups  or other countries where COVID-19 measures may have been different, but also the lifestyle and aspirations of young adults may be different from Germany ,31. The Notwithstanding these limitations, during the COVID-19 lockdowns in Germany, significant reductions in mood, quality of life, and perceived immune functioning were reported. However, these effects were significantly more pronounced among individuals with self-reported impaired wound healing compared to healthy controls.


There is an increased incidence of elderly adults diagnosed with kidney failure as our global aging population continues to expand. Hence, the number of elderly adults indicated for kidney replacement therapy is also increasing simultaneously. Haemodialysis initiation is more commonly observed in comparison to kidney transplantation and peritoneal dialysis for the elderly. The onset of the coronavirus 2019 (COVID-19) pandemic brought new paradigms and insights for the care of this patient population. Elderly patients receiving haemodialysis have been identified as high-risk groups for poor COVID-19 outcomes. Age, immunosenescence, impaired response to COVID-19 vaccination, increased exposure to sources of COVID-19 infection and thrombotic risks during dialysis are key factors which demonstrated significant associations with COVID-19 incidence, severity and mortality for this patient group. Recent findings suggest that preventative measures such as regular screening and, if needed, isolation in COVID-19-positive cases, alongside the fulfillment of COVID-19 vaccination programs is an integral strategy to reduce the number of COVID-19 cases and consequential complications from COVID-19, particularly for high-risk groups such as elderly haemodialysis patients. The COVID-19 pandemic brought about the rapid development and repurposing of a number of medications to treat patients in the viral and inflammatory stages of their disease. However, elderly haemodialysis patients were grossly unrepresented in many of these trials. We review the evidence for contemporary treatments for COVID-19 in this population to provide clinicians with an up-to-date guide. We hope our article increases awareness on the associations and impact of COVID-19 for the elderly haemodialysis population, and encourage research efforts to address knowledge gaps in this topical area. Emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, responsible for the coronavirus 2019 (COVID-19) pandemic outbreak, has since had a profound impact on health systems globally ,4,5,6,7.2 is considered one of the strongest predictors for poor clinical outcomes [Advancing age is associated with an increased likelihood of contracting COVID-19 infection, with adults above 80 years of age particularly being at greatest risk . The hazoutcomes ,12. Mortoutcomes . The risoutcomes ,14. TherIn a vast cohort study undertaken by National Health Service England, nearly 1000 COVID-19-related deaths were reviewed. Age by far was the greatest predictor of mortality, and most comorbidities were associated with increased mortality risk, particularly cardiovascular disease and diabetes. These are both common comorbidities amongst the dialysis population . In anotFrailty is a significant health burden for elderly patients with advanced CKD and those with kidney failure requiring dialysis treatment ,17. FraiImmunosenescence refers to the changes to the immune system that occur with aging, leading to an increased prevalence of infections, malignancy and autoimmune diseases . Both T Immunosenescence is likely prevalent within the elderly haemodialysis population . The perNot only are elderly haemodialysis patients at increased risk of contracting and having worse outcomes from COVID-19 infection, but their response to COVID-19 vaccination is also inferior compared with healthy controls . This isSARS-CoV-2 is a respiratory pathogen, spread via aerosolized droplets. It is highly contagious with an R0 of 2.2 with the degree of risk for infection related to exposure and proximity to an infected individual . Many coCOVID-19 is known to induce a state of hypercoagulability and endothelial dysfunction that correlates with the degree of inflammation . This meThere were increased efforts to implement COVID-19 preventative measures specific to elderly haemodialysis patients, due to the increase risk of these patients contracting COVID-19 from their frequent contact and interactions with other dialysis patients and healthcare staff if receiving in-centre dialysis and a high-case fatality from COVID-19 compared to the general population.Strategies to prevent patient-to-patient transmission of COVID-19 may include the implementation of regular screening programs. Two types of screening programs can be employed: symptom-based screening followed by specific testing or a universal screening program. The screening process can vary based on the type of test used, such as nasal polymerase chain reaction (PCR), antigen testing or serum antibody testing, and screening programs may also differ based on the frequency of screening.The International Society of Nephrology COVID-19 guidelines has recommended symptom-based testing as a method to identify and reduce the transmission of COVID-19 in patients with CKD, in particular those receiving dialysis . A studyIn another study that used the widely available rapid antigen tests (RAT), 277 haemodialysis patients were screened from 15 February 2021 to 15 November 2021. Thirty-eight tests were returned positive, but only five (14%) cases were subsequently confirmed as COVID-19 positive by PCR testing. Over this period, 6.4% of the haemodialysis population had contracted COVID-19, with routine RAT picking up 27.7% of the cases . A similAlthough RAT is able to identify asymptomatic COVID-19-positive cases and is cheaper to perform compared with PCR testing, it may not be sensitive enough to pick up an adequate number of cases. Data on PCR screening programs in haemodialysis populations are less well documented, but in one study, 200 patients were screened using PCR testing over a five-day period in early 2020 in a dialysis unit in France. Of these, 19% of patients had a positive result returned from their PCR test, and of those with a positive test result, 10% were asymptomatic . If readIt should be acknowledged that the clinical phenotype of COVID-19 has changed over time through the natural history and evolution of the virus and the increased delivery of vaccination. Esposito and colleagues highlighted that a cohort of COVID-19 haemodialysis patients in September 2021–February 2022, when compared to COVID-19 haemodialysis patients in March-December 2020 experienced less severe illness, though there were greater frequencies of asymptomatic disease . This haOnce COVID-19-positive individuals receiving haemodialysis have been identified, it is important to cohort infected patients together to prevent a further spread of COVID-19 around the dialysis unit. The timeframe which presents the greatest risk of COVID-19 infection spread is within a dialysis session in which there are COVID-19-positive patients, in which horizontal transmission is commonly observed particularly in small in-centre dialysis venues where there are the greatest rates of infectious transmission . There aThe time recommended for elderly haemodialysis patients to remain isolated if COVID-19-positive test results were found is also longer than the general population. This is based on findings that the average time to a first negative test for kidney failure patients is 7 days longer than someone without kidney failure . Over 65While most haemodialysis patients experience a durable immune response following a full COVID-19 vaccination schedule that is comparable to the general population, there is evidence to suggest that those with higher initial antibody titres exhibit a more prolonged response ,81,82,83In the current landscape of vaccine development for the prevention of COVID-19, two principal categories of vaccines have emerged: mRNA vaccines and adenovirus vector vaccines. The former includes the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 vaccines (Moderna), while the latter encompasses the AZD1222 (AstraZeneca) and Ad26.COV2.S vaccines (Johnson & Johnson). The mRNA vaccines function by delivering genetic instructions for producing the viral spike protein to the host cell through the use of lipid nanoparticles, while the adenovirus vector vaccines rely on the use of modified adenoviruses to deliver genetic material for spike protein production to the host cell. Though both types of vaccines have demonstrated efficacy and safety in clinical trials involving the general population, and their widespread use has played a pivotal role in mitigating the ongoing COVID-19 pandemic, emerging data suggest that antibody responses to COVID-19 vaccination may differ amongst the various vaccination brands in elderly haemodialysis patients.The adenovirus vector vaccine AZD1222 (AstraZeneca) has demonstrated reduced immunogenicity in patients receiving haemodialysis, in comparison to the mRNA BNT162b2 (Pfizer-BioNTech) vaccine . Whilst In regard to the frequency of COVID-19 vaccination for elderly haemodialysis patients, previous studies have demonstrated that antibody levels in the general population following COVID-19 vaccination begin to decline approximately six months post-inoculation, with subsequent increased risk of infection but providing continued protection against risk of complications leading to hospitalization and mortality ,88. TherNumerous medications have been proposed or developed during the pandemic in an effort to find treatment options for COVID-19, and to explore how patient outcomes could be improved. In a broad sense, therapeutics could be classified into two categories: antiviral and anti-inflammatory treatments. Antiviral treatments are aimed towards patients in the pre-hospital setting, during the early viral replication phases of their disease course. In contrast, anti-inflammatory treatments are intended for patients acutely unwell in the hospital setting, typically those requiring oxygen therapy, and those who exhibit signs of pneumonitis, with the goal of attenuating the cytokine/hyperinflammatory response. Due to the rapid emergence and evolution of COVID-19 pandemic data, discussion of all antiviral treatments that have been developed during the pandemic is beyond the scope of our review, as many antiviral treatments were eventually found to be ineffective and the Omicron variant with its numerous mutations in the spike protein has rendered many previous treatments obsolete. We will focus on treatment options that have received approval from the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH) and the National Institute for Health and Care Excellence (NICE) and discuss key trial findings, as well as evidence in relation to their use, efficacy and adverse effects within the context of elderly patients, patients with kidney disease and those receiving haemodialysis .Nirmatrelvir and ritonavir (Paxlovid) is a boosted 3cl protease inhibitor. It has been trialed in the EPIC-HR study which was a randomized trial which administered 300 mg of oral nirmatrelvir and 100 mg of oral ritonavir every 12 h for 5 days, or a placebo in non-vaccinated COVID-19-positive patients pre-hospital admission. The primary outcome of the study was risk of hospital admission or death from any cause . The stuRemdesivir functions via its incorporation into viral RNA and termination of RNA transcription. This drug was trialed in the PINETREE study, a randomized controlled trial in which intravenous remdesivir (200 mg on day 1 and 100 mg daily on days 2 and 3) was compared with a placebo in non-vaccinated patients in pre-hospital settings . The priIn another retrospective cohort study conducted between January and March 2022, 118 haemodialysis inpatients with positive COVID-19 tests were evaluated . The meaMolnupinavir is a prodrug of N-hydroxycytidine (NHC), a nucleoside analogue. It has been trialed in two randomized clinical trials—the MOVe-OUT trial and another study by Fischer and colleagues compared clinical outcomes in pre-hospital non-vaccinated patients taking 800 mg of molnupiravir for 5 days versus placebo ,98. The There are few studies which investigated the efficacy of molnupiravir in the context of the dialysis population. Poznansk and colleagues presented a retrospective cohort study reporting on the use of molnupiravir in 20 dialysis patients with positive COVID-19 test results . These p2. Another retrospective analysis of haemodialysis patients with COVID-19 infection receiving dexamethasone did not demonstrate a clear clinical benefit [The RECOVERY trial aimed to evaluate the effectiveness of administering 6mg of dexamethasone for 10 days to adult patients diagnosed with COVID-19 infection . Among a benefit . HoweverThe interleukin-6 (IL-6) inhibitors, tocilizumab and sarilumab, have demonstrated reductions in all-cause mortality amongst hospitalized adults with COVID-19 when used with the standard care that was described in the RECOVERY and REMAP-CAP trials ,103. Toc2 and unfortunately, the use of baricitinib is currently not recommended for patients on dialysis. A phase 2 trial is currently underway to investigate its use in patients with diabetic kidney disease [Baricitinib, a Janus kinase (JAK) inhibitor, was shown to be beneficial for hospitalized patients diagnosed with COVID-19 infection in the RECOVERY trial . Importa disease .The PROTECT-V (PROphylaxis for paTiEnts at risk of COVID-19 infecTion) study is a clinical trial aimed at evaluating the effectiveness of intranasal niclosamide prophylaxis in preventing COVID-19 infection . NiclosaEvidence regarding the associations between COVID-19 and clinical outcomes in dialysis patients, particularly the elderly haemodialysis population, has certainly increased since the onset of the pandemic. Our understanding of the various factors which contribute towards increased risks of contracting COVID-19 infection and disease severity for this vulnerable patient population has been broadened with the emergence of basic and clinical trial research within this topical area. Widening the recruitment and sub-study of the elderly haemodialysis population in ongoing COVID-19 clinical trials over time may further inform the long-term implications of COVID-19 for this patient group. It is encouraging that at a local, national and international level, there have been preliminary data to establish directive guidance for the prevention and medical treatment of COVID-19 infection in dialysis patients.


Since April 2020, mink have been recognized as a potential reservoir for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a potential source of new variants. The objective of this report is to describe the epidemiological investigation and public health response to two coronavirus disease 2019 (COVID-19) outbreaks that involved both humans and farmed mink.An outbreak was declared on December 4, 2020, following detection of two COVID-19-positive farmworkers and elevated mink mortality on a mink farm (Farm 1) in British Columbia. The second cluster was detected on Farm 3 following detection of 1) a COVID-19 case among farm staff on April 2, 2021, 2) an indeterminate result from farm staff on May 11, 2021, and 3) subsequent SARS-CoV-2-positive mink in May 2021. Quarantine of infected farms, isolation of workers and their close contacts, and introduction of enhanced infection control practises were implemented to break chains of transmission.Among mink farmworkers, 11 cases were identified at Farm 1 and 6 cases were identified at Farm 3. On both Farm 1 and Farm 3, characteristic COVID-19 symptoms were present in farm employees before signs were observed in the minks. The viral sequences from mink and human samples demonstrated close genetic relation. Phylogenetic analyses identified mink intermediates linking human cases, suggesting anthropo-zoonotic transmission.These were the first COVID-19 outbreaks that included infected mink herds in Canada and identified potential anthropogenic and zoonotic transmission of SARS-CoV-2. We provide insight into the positive impact of regulatory control measures and surveillance to reduce the spillover of SARS-CoV-2 mink variants into the general population. Mink—a semiaquatic, carnivorous mammal of the genus Neogale—have been identified as a potential reservoir of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) . GenetiThe Fraser Valley contains all mink farms in British Columbia (BC), Canada, and produced 23% of Canadian mink pelts in 2020 . BC’s fWe report on the epidemiological investigation of the two outbreaks that involved genetically linked human and mink infections with SARS-CoV-2 occurring between December 2020 and November 2021 in BC. We reflect on the impact of control measures, vaccines and active surveillance, highlighting how these interventions may have created the unique epidemiological profile observed on Farm 3 and provide comparisons to Farm 1 and other outbreaks described in the literature.The outbreak on Farm 1 was detected on December 2, 2020, during the pelt-harvesting season after two farmworkers tested COVID-19-positive at a community testing site. The farm owner identified an increased overall mortality rate of approximately 1.5% in the herd of 15,000 mink in the preceding week. A herd veterinarian was deployed to sample mink mortalities on the farm. On December 4, 2020, Public Health (PH) declared an outbreak in mink and farmworkers and the Ministry of Agriculture, Food and Fisheries (MAFF) quarantined the farm after four of five mink samples tested non-negative. On February 24, 2021, the outbreak was declared over.On April 2, 2021, a farmworker on Farm 3 tested positive prior to achieving vaccine-mediated immunity through the mink farmworker surveillance system established in February 2021 . On MayThe British Columbia Centre for Disease Control (BCCDC) Public Health Laboratory conducted real-time polymerase chain reaction-based (RT-PCR) SARS-CoV-2 testing using RdRP and E gene targets; specimens were confirmed SARS-CoV-2 positive at a cycle threshold (Ct) value ≤35. The MAFF performed preliminary animal testing (reported as negative or non-negative based on RT-PCR of the E gene target) that was confirmed with similar assays validated in animals at the National Centre for Foreign Animal Disease laboratory in Winnipeg, Canada.All human and animal samples with a PCR-confirmed positive test underwent next-generation whole genome sequencing (WGS) using laboratory methods described in detail elsewhere . BrieflFor these investigations, the case definitions were as follows:and had a positive RT-PCR (Ct:≤35)Confirmed case: an individual who worked on the farm and had an indeterminate RT-PCR (Ct:36–50) and reported respiratory symptoms consistent with SARS-CoV-2 in the two weeks prior to testing or was a household contact of a confirmed caseEpidemiologically linked case: an individual who worked on the farm Public Health conducted investigations of confirmed cases within 24 hours of notification. Interviews explored illness onset date, symptoms, exposure history, risk factors, close contacts and connections to other mink farms. Owners of infected farms confirmed each case’s duties and identified farm contacts. Cases were instructed to isolate for 10 days. Close contacts of SARS-CoV-2-positive mink and humans were advised to self-isolate for 14 days since their last exposure and seek testing if symptoms developed.et al.  software. The crude attack rate for secondary cases is the number of confirmed cases over the number of susceptible persons (i.e. close contacts who were not employed on the farm). Shared contacts were counted once.The provincial One Health Committee, detailed in The One Health Committee provided instructions for animal care, including minimizing interaction length and frequency, limiting care to asymptomatic individuals, and enhanced hand hygiene. Enhanced biosecurity measures for mink care included the use of full personal protective equipment , the establishment of a quarantine zone for donning and doffing personal protective equipment, and sanitation procedures for soiled boots and gloves. Surgical masks were sufficient when not in close proximity to mink.Three recovered farmworkers were permitted to euthanize the herd for the purposes of pelt production December 16–24 2020, as pelting would remove infected mink and reduce risk of further transmission. Breeding stock was retained. All euthanized mink were stored in the farm freezer for later processing. Farmworkers involved in pelting were released from isolation 14 days after the last mink was euthanized. Following pelting, no SARS-CoV-2 was detected in the herd.While the response to the Farm 3 outbreak had many similarities to Farm 1, the most significant difference in the two responses was the presence of industry-wide, preventative measures and surveillance infrastructure that was established from mid-December 2020 to April 2021. These measures included the creation of a weekly voluntary human surveillance system to detect asymptomatic or pre-symptomatic cases among farmworkers, as well as public health mandates to ensure weekly testing of mink mortalities, enhanced biosecurity measures (as described for Farm 1) and farmworker vaccination .In addition to the above measures, PH required all Farm 3 workers exposed to the mink herd to follow a work-home quarantine May 11–June 9, 2021. The voluntary farmworker screening was increased to 2–3 times a week. Concurrent environmental health inspections found an acceptable compliance with the newly established provincial-level biosecurity requirements.There were 11 cases among 12 farmworkers  associated with the Farm 1 outbreak  within the AW.1 lineage, a lineage circulating locally in October 2020  despite a similar workforce size  and loweFive of six human samples and 79 mink samples generated high-quality sequence data and were included in the phylogenetic analysis . Human aThis report summarizes two COVID-19 outbreaks among mink farmers and their livestock in Canada. On both farms, symptoms were present in staff before detection in the minks, viral sequences from mink and human-derived isolates were closely related, and human cases predominantly arose during periods of higher human-mink contact . These findings point to a likely anthropogenic introduction of SARS-CoV-2 into farmed mink by farm staff, viral evolution in the mink host and then reintroduction into human hosts. Variations in the length and transmission patterns observed between outbreaks may be attributable to the different PH measures in place at each outbreak’s onset.The rapid transmission observed on Farm 1 may be credited to late detection, the absence of natural or vaccine-mediated immunity among farmworkers and mink and ineffective biosecurity control measures. Factors resulting in late outbreak detection included self-initiated community testing and early spread among the co-housed migrant workforce, a population well recognized for limited access to health services ,16). Alt. Alt16))The late detection of the Farm 1 outbreak makes it difficult to establish the date of introduction onto the farm and chain of transmission, which could plausibly have begun weeks earlier than the index case. While it is challenging to establish directionality of transmission for all cases, the WGS analysis strongly suggests two human cases acquired SARS-CoV-2 from mink. Mink-to-human transmission is further supported by the rapid genetic divergence observed on Farm 1, which is beyond the approximate one mutation per two weeks expected through human-to-human transmission alone .The absence of related co-circulating community strains, dispersal of human cases in time, epidemiology and WGS pointed to multiple transmissions from mink to fully vaccinated humans over seven months at Farm 3. Although other outbreak reports have suggested outbreaks in farmed mink can run their course quickly ,6), Farm, Farm6))The absence of spillover into the community stemming from Farm 3 illustrates the potential importance of provincial policies enacted in BC that led to the development of early outbreak detection systems, enhanced biosecurity measures and early vaccination of mink farmers and their households . SpecifThe strengths of this outbreak investigation included the adoption of a One Health approach that integrated multiple agencies to respond to a pathogen with demonstrated capacity for human spillovers. Comprehensive, frequent testing of staff during outbreaks makes the likelihood of undetected human intermediary cases remote.There are several limitations to this report. Data on symptoms and close contacts were self-reported and vulnerable to social desirability and recall bias. Due to concerns about economic, logistical and reputational impacts, farmworkers and owners may have been hesitant to report a large number of contacts. It is difficult to ascertain a causal relationship between individual initiatives and their effects on controlling each outbreak given the application of multiple interventions. Despite these limitations, this report adds to the literature of the emerging threat of SARS-CoV-2 in mink reservoirs and describes the actions that led to the interruption of the chain of transmission of mink variants in the largest health authority in British Columbia.These outbreaks provide additional evidence of zoonotic transmission of SARS-CoV-2 from mink to humans and the potential for subsequent community spread. The second outbreak at Farm 3 demonstrated that the risk of human acquisition can persist for months during longer outbreaks in mink herds. Biosecurity requirements, staff vaccination and an ongoing surveillance system contributed to reducing the spillover of mink variants into the general community; however, these measures were unable to eliminate the risk of mink-to-human transmission during persistent herd infections. These outcomes provide evidence for other jurisdictions of the importance of active surveillance to support timely response to SARS-CoV-2 in these high-risk settings. A One Health approach is needed to successfully respond to outbreaks involving humans and animals, as experts in various fields must collaborate to limit disease spread.


Self-assembly of particle-like dissipative solitons, in the presence of mutual interactions, emphasizes the vibrant concept of soliton molecules in varieties of laser resonators. Controllable manipulation of the molecular patterns, held by the degrees of freedom of internal motions, still remains challenging to explore more efficient and subtle tailoring approaches for the increasing demands. Here, we report a new phase-tailored quaternary encoding format based on the controllable internal assembly of dissipative soliton molecules. Artificial manipulation of the energy exchange of soliton-molecular elements stimulates the deterministic harnessing of the assemblies of internal dynamics. Self-assembled soliton molecules are tailored into four phase-defined regimes, thus constituting the phase-tailored quaternary encoding format. Such phase-tailored streams are endowed with great robustness and are resistant to significant timing jitter. All these results experimentally demonstrate the programmable phase tailoring and exemplify the application of the phase-tailored quaternary encoding, prospectively promoting high-capacity all-optical storage. Here the elementary pulse entity, termed ‘dissipative solitons’ in contrast to the ‘pure solitons’ formed in conservative systems, originates from the dual interplays between the dispersion/nonlinearity and gain/loss9. Intriguingly, these ultrashort soliton entities can behave like particles and self-assemble into bound states of complex structures, endowed by the balanced interaction forces13. The parallel concept of ‘matter molecules’ is transferred into the multisoliton complexes, and many unveiled internal motions emphasize this light-matter analogy, which spreads the profound concept of dissipative soliton molecules (DSMs)14. Considering the increased complexity beyond the single entity, soliton molecules display more plentiful internal dynamics in the presence of energy exchange between each constituent, as well as would allow enhanced coding of optical-soliton bits19. Recent use of time-stretch dispersive Fourier transform (TS-DFT) based real-time spectral interferometry enables long-lasting studies on the transient multisoliton dynamics19. The degrees of freedom of molecular internal motions are anticipated by resolving the temporal separations and relative phases, in response to how far the molecular analogy reaches26. For applied stimuli, dynamic soliton molecules can support high-order encoding formats of all-optical information processing beyond the pulse-counting formats. This foresight of alternative encoding scheme is held by the precise switching between each bound state, arousing one striking question of programmable generation and control of molecular dynamics27.Streams of ultrashort light pulses delivered from mode-locked laser resonators stimulate potential applications in ultrafast science and information technology28. Soliton constituents can be globally ordered and locally spaced to form a supramolecular structure by tailoring long-range soliton interactions of different origins10. This panoramic scenario allows for the assemblies of soliton–soliton, soliton–molecule or molecule–molecule under controllable intra-molecular dynamics, with respect to the time scales ranging from tens of picoseconds to hundreds of picoseconds. While staring at the solitonic bound states down to several picoseconds even sub-picoseconds, precise manipulation of intra-molecular dynamics emerges into the scientific spotlight, echoing the degrees of freedom towards temporal separations and relative phases29. In consideration of the energy exchange within molecular structures, direct pump modulation is exploited to harness the multisoliton interactions for a rapid switching between discrete binding states, principally referring to the temporal separations30. Recent parallel work further performs on-demand harnessing of soliton molecules between each predetermined value of the temporal separation by varying the second-order group-velocity dispersion and dispersion losses32. Quaternary encoding and switching of soliton molecules are proposed beyond the binary format. These temporal-separation-switched intra-molecular manipulations would make these ‘potential applications’ realizable, as well as appealing to explore subtler assembly and control of soliton molecules, fueled by the degrees of freedom of internal dynamics, especially applicable to multiple encoding formats for all-optical storages.Temporal optomechanical lattice induced trapping potentials enable an all-optical assembly of large soliton sequences in a photonics crystal fiber-based fiber laser resonator39. Intrinsic insights into the mutual interactions reveal the scenarios of energy exchange within the binding structures, which emphasizes the inevitable routes for controlling the assembly of molecular patterns. Viewed from the real-time spectral interferometry, which is regarded as the ‘eyes’ in controllable laser systems, the fringe pattern is modified by external perturbations, generally indicating the beginnings of temporal-separation variations, synthesis and dissociation processes40. With regard to the superiority of the dynamic indicator and the applied foresights, the programmable tailoring of molecular phases is expected to be fuel debate; however, it is barely experimentally achievable for laser resonators. In this paper, we pursue a new quaternary encoding format based on the programmable tailoring of the internal dynamics of DSMs. Controllable manipulation on the energy exchange enables deterministic harnessing of soliton assemblies, accordingly developing four phase-defined regimes. By implementing electronic modulation of the gain supply, continuous switching among these regimes is realized, validating the reversibility and high fidelity of the programmable tailoring. In addition, the recorded real-time streams exemplify the availability of this phase-tailored encoding, which is highly desirable for multiple encoding and switching.The on-going discovery of internal molecular dynamics, via using the advanced spectral observations, in essence, can enrich the manipulation mechanism of soliton molecules14. Versatile internal motions are governed by the energy exchange between two adjacent constituents, which is important for phase-dominated soliton dynamics11. A real-time monitoring module is utilized to identify these particle-like behaviors by retrieving the temporal distributions and internal motions. Such particle-like behaviors can be harnessed by the tunable intracavity gain supply. High-speed electronic modulation of the gain supply is introduced to stimulate the artificial manipulation on the temporal assembly and internal assembly of DSMs   Fig. .Fig. 2PhφNP, φSP, φPP) indicate the different pulse intensity relations between the two constituents   Fig. . In partSequentially, programmable electronic modulations of the gain supply are implemented to harness the phase-tailored assemblies of the DSMs. These internal phase dynamics are mainly affected by the gain dynamics, pulse intensity relations and energy exchanges between the two adjacent constituents Fig. . To illu5,31. Programmable tailoring of the molecular phase is implemented for multiple encoding. Beyond the pulse-counting-based binary encoding , including a 100-μs for valid data and another 100-μs for the hysteresis process Fig. . The speTo verify the availability of this phase-tailored quaternary encoding, an exemplary ‘fiber’ is encoded into real-time streams and decoded by retrieving the molecular phase Fig. . In eachg0 actuate the deterministic harnessing of the molecular phase of DSMs. The simulation results reveal the exact relations between the phase evolutions and the pulse intensities. In practice, the exemplary string {f|i|b|e|r} is presented to experimentally validate the availability of this phase-tailored quaternary encoding.The controllable manipulation of the molecular patterns still remains challenging to explore more efficient and subtle tailoring approaches for satisfying the increasing demands. Apart from the temporal-separation-based harnessing of the molecular patterns, the molecular phase of DSMs is also expected to be harnessed. Recent studies of transient soliton dynamics provide strong supports for guiding the artificial manipulation on the molecular phase. Here, inspired by advanced applications of ultrafast optics in all-optical storage and optical computations, we develop an ultrafast laser-based manipulation system for the programmable tailoring of the molecular phase by implementing precise electronic modulations of the gain supply. The energy exchange within the molecular structures is manipulated to stimulate the deterministic harnessing of the phase-tailored soliton assemblies. Self-assembled soliton molecules are tailored into four phase-defined regimes, thus constituting the phase-tailored quaternary encoding format. Numerical simulations of the switching among different phase-defined regimes are conducted to confirm and interpret the physical mechanism of the programmable phase tailoring  and the accurate identification of the encoded formats. In particular, this direct electronic modulation can be improved by upgrading the electronic modulation signals to avoid the common recoil voltage and unstable voltage. The well-set voltages for these four phase-defined regimes can optimize the hysteresis of the continuous switching and the fidelity of the phase-tailored encoding. For increasing the speed of the quaternary encoding, faster phase-evolving velocities of the NP and PP regimes can be taken into account. Thus, we believe that the electronic modulation of the gain supply is considered as a direct and efficient way to realize the programmable tailoring of the molecular phase of the DSMs, and desirable for the applications in practical occasions.41, the extended temporal-phase evolutions may accommodate more information for high-capacity all-optical storage. Naturally, the released degrees of freedom of the on-demand harnessing will bring about significant challenges for both the ‘eyes’ of the real-time characterization and the ‘hands’ of the precise manipulation. We consider two major avenues for the future investigations. One is to introduce the joint temporal-spectral analysis of the time-stretch dispersive Fourier transform and the time-lens measurements. The real-time full-field characterization can provide new insights into the internal motions, especially for the complex molecular patterns. ‘Hands’ can help control the laser parameters such as the gain, dissipation, dispersion, nonlinearity and polarization to drive the artificial manipulation. The released degrees of freedom of harnessing and the technical advances are expected to fuel this research topic and extend the application scenarios in the near future.For the moment, the topic of on-demand harnessing is currently driving considerable attentions. Based on the research thought that the transient dynamics guide the artificial manipulation on DSMs, we expect the lasting investigations by releasing the harnessing degrees of freedom. Particularly, more internal motions can be anticipated for enabling the artificial manipulation. The phase-evolving velocity can be quantified to encode information beyond the four phase-defined regimes. Moreover, the programmable tailoring of the temporal assemblies and the internal assemblies of DSMs allows for the higher-order encoding formats. While considering the molecular patterns with increased number of solitons such as the tri-soliton assembly and the quartic-soliton assemblyβ2 = +0.061 ps2 m−1, EDF 80, OFS) as the gain medium and a 2.9-m single-mode fiber . The cavity repetition rate of the fiber laser resonator is about 54.86 MHz. The NPR based mode-locking module is composed of a polarizer and two polarization controllers (PCs). The ultrafast fiber laser resonator with near-zero dispersion provides an abundant platform for investigating the phase-tailored soliton assemblies and the quaternary encoding.We investigate the programmable tailoring of the molecular phase of DSMs, which are generated from the ultrafast fiber laser resonator. The pump energy is programmed by implementing electronic modulations of a 980-nm semiconductor laser diode and is then injected into the laser resonator through a hybrid module, which is integrated by a wavelength division multiplexer (WDM), a 10:90 output optical coupler (OC) and an isolator (ISO). The emitted optical pulses are extracted from the 10% output port. The total length of laser resonator is 3.7 m, including a 0.8-m erbium-doped fiber  is used as a dispersive medium with a total dispersion of −220 ps2 for the time-stretch process. For soliton pairs with a temporal separation τ, the spectral modulation period 1/τ of the optical spectrum is mapped into the time domain and stretched to −1, Teledyne LeCroy) are utilized to detect the successive spectral evolution of DSMs. And an optical spectral analyzer  is used to monitor the optical spectrum for comparison. The first-order autocorrelation traces are calculated from the successive spectral interferograms by performing fast Fourier transform. The separation information and phase information (imaginary part) are extracted from the peaks of the first-order autocorrelation traces. However, the extracted phase information is in the range of  and cannot represent the real internal phase evolution. The phase unwrapping is introduced to make the extracted phase information continuous by adding 2kπ. If the variation of two phases is over π rad, it is regarded as phase jump. The retrieved molecular phase should be consistent with the evolution of the spectral fringes in successive spectra interferograms. In particular, phase ambiguity is also important in the phase retrieval, especially during the switching between different soliton assemblies. The assembly and dissociation of soliton assemblies follow very complex dynamics and are represented by the rapid spectral evolution and unstable temporal separation, consequently resulting in the phase ambiguity10. Recent study has reported on machine learning strategies to reconstruct the multisoliton dynamics without the phase ambiguity, which have potential applications in ultrafast science18.A 10-km SMF (−1. Appropriate voltages related to the four phase-defined regimes are set to realize the high fidelity of the phase-tailored encoding. The direct electronic modulation can be upgraded to avoid the uncontrollable fluctuations of the gain supply, which is commonly induced by the recoil voltage and unstable voltage. Relying on the ASCII-based phase-tailored alphabet, arbitrary encoding can be realized by implementing the precise electronic modulation of the gain supply.An AFG with a modulation bandwidth of 25 MHz is utilized to generate the electronic modulation signals. The emitted pump power is modulated by the electronic signal with a transfer efficiency of 52 mW Vz, T, β2, γ are the propagation coordinate, pulse duration, second-order dispersion parameter and nonlinear parameter, respectively; Ωg is the gain bandwidth; g is the gain coefficient, modeled by g0 is the small signal gain that is non-zero only for the EDF; Psat is the gain saturation power; Pave is the averaged power of pulses.To confirm and better interpret the mechanism of the phase-tailored soliton assemblies, numerical simulations are executed through a piecewise pulse propagation model in the scalar approach, which takes into account the different segments in the fiber laser resonator. The propagation model follows the extended nonlinear Schrödinger equation:a0, I, Isat, ans are the modulation depth, input intensity, saturation intensity and non-saturable absorbance, respectively. We emulate the experimental situation by adjusting the parameters of the fiber laser resonator. The internal phase evolution is retrieved from the successive spectral evolution.The saturable absorber in the fiber laser resonator is modeled by a transmission function: Supplementary Information


What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20)  and the Health Assessment Questionnaire—Disability Index (HAQ-DI) , and within the equivalence margins: ACR20  and HAQ-DI . The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis. Biosimilars are complex molecules intended to be highly similar in terms of quality, safety, and efficacy to an already licensed drug (referred to as a reference biologic drug)4. The use of tumour necrosis factor inhibitors (TNFIs) biosimilars for patients using biologic disease-modifying antirheumatic drugs has been the standard of care for rheumatoid arthritis in areas of the world where biosimilars are available5. In situations where a patient will have their treatment exchanged or replaced by another treatment, the decision-making on switching should be based on the best level of evidence available1.Biosimilars have emerged into the global market as a cost-saving option and have taken their place in the optimization of the current clinical management of rheumatoid arthritis, a lifelong disease that can lead to severe joint damage and disability9. In clinical practice, concerns arose with switching which possibly could lead to increased immune reactions, loss of efficacy, and/or more risk of safety issues10. There is no scientific rationale to support or refute these concerns1. Multiple switching studies have been reported with the conclusion that switching between reference biologics and biosimilars is reasonable11 and some authors have argued that there is already available a large body of clinical studies on switching that would be enough to convince the medical community about the switching of reference biologics and biosimilars12. Previous systematic reviews have attempted to gather this evidence, but most of the results are either descriptive or qualitative17, and the unique pooled estimates available included a restricted number of trials and participants18.The key question about biosimilars is whether switching from the reference biologic to a biosimilar or within multiple switching scenarios would affect the response to the treatment20. A standard meta-analysis restricted to head-to-head comparisons would be not suitable for comparisons of multi-arms trials. In this case, network meta-analysis (NMA), which is a generalization of pair-wise meta-analysis, can be used to synthesize a greater share of the available evidence and provide clinically relevant estimates to better support decision-making22. Therefore, we aimed to assess the impact of switching on the treatment of rheumatoid arthritis through a network of evidence of head-head comparisons of switching and non-switching arms of TNFi biologics and biosimilars.The typical switching study involves a three-arm trial in which patients in the reference biologic group are re-randomized either to continue in the biologic group or to switch to the biosimilars and in parallel, patients initially allocated to the biosimilar group continue to receive a biosimilar throughout the study period20 for two objectives: 1) efficacy and safety (objective 1) and switching (objective 2). Results regarding objective 1 have been published elsewhere23. Here, we present the study for objective 2. All changes in the protocol were explicitly mentioned as ad-hoc modifications  and published a single protocolEligible participants were patients with rheumatoid arthritis. Interventions of interest were biosimilars of adalimumab, etanercept, and infliximab. Comparators of interest were the reference biologic drugs . We included randomized controlled trials (RCT) or quasi-RCT that had at least a period (re-randomized or the open-label extension) assessing the impact of switching between treatments. Two investigators independently assessed titles, abstracts, and full-length articles against the eligibility criteria. The full description of eligibility criteria and selection process are given in Supplementary Methods file 3 and Table The detailed evidence sources and search strategy are provided in Supplementary Methods file 4. We systematically searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Latin American and Caribbean Health Science from database inception to April 2021. We also searched for unpublished/ongoing trials in four trial registry databases and performed citation searches.25.The data collection process and the list of variables extracted are shown in Supplementary Methods file 5. Briefly, two reviewers independently extracted all pertinent quantitative data per study arm. If available, we used data referred to as the Per-Protocol (PP) population as it is the most conservative approach to assess equivalence between treatments20 In summary, we assessed the impact of switching on efficacy (encompassing clinician and patient-reported outcomes), safety, and immunogenicity. For this study, the time point of interest for all outcomes is at 6 months after the first switch . If efficacy outcome data were reported at different time points, we used the time point closest to 6 months after the first switch.We previously prespecified the outcomes of interest elsewhereThe prespecified primary efficacy endpoint was the treatment success at 6 months after the first switch, according to the American College of Rheumatology 20% response criteria (ACR20). We prespecified as a co-primary outcome the Health Assessment Questionnaire—Disability Index (HAQ-DI) 6 months after the first switch (see Supplementary Methods file 6 for details).As prespecified, we assessed seven secondary outcomes that capture disease activity, one measures functional capacity/quality of life, and one assesses structural damage (Supplementary Methods file 7).The prespecified safety and immunogenicity outcomes included: the proportion of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, special adverse events, mortality, overall discontinuation rates, positive anti-drug antibodies (ADAs) formation, and positive neutralizing antibodies (Nabs) (further details see Supplementary Methods file 8).26 and the Food Drug Administration guidance19 to assess the risk of bias across six specifics domains of switching trials: (1) Randomized and blinded design with appropriate control arms; (2) At least 1-way switch from originator to a biosimilar; (3) The assessment of immunogenicity; (4) The washout period between treatment; (5) Enough power to assess efficacy and safety , and (6) Enough follow-up periods. A detailed description is given in Supplementary Methods File 9 and Table We used the recommendations of Moots et al.Ref → Ref patients taking reference biologics drugs continued the treatment (non-switching group).Bios → Bios patients taking biosimilars continued the treatment (non-switching group).Ref → Bios patients taking reference biologics drugs switched to biosimilars (switching group).Bios → Ref patients taking biosimilars switched to reference biologics drugs (switching group).We identified four general types of switching and non-switching groups in the included trials as follows:Our NMA model provides six or three possible pairwise comparisons estimating the comparative efficacy, safety, and immunogenicity within and between switching and non-switching groups. We treated the multi-arm studies as multiple independent two-arm studies in NMA. We assessed the transitivity (similarity) assumption by comparing the main methodological and clinical characteristics across all eligible trials by arm level. A network plot linking the switching and non-switching arms of biosimilars, and reference biologics drugs was constructed to indicate the level of pair-wise comparison.27. We selected the Bayesian random effect model for NMA as the primary analysis because it is usually the most conservative option and Bayesian estimates can be interpreted in terms of probabilities and give a framework that supports decision-making21.We conducted a pairwise and NMA with multi-arm trials within a Bayesian random-effects framework and a frequentist fixed-effects approach which both accounted for the correlation between the treatment difference effect for each group of multi-arm trialsThe approaches to approximate means and standard deviations from the reported statistics are shown in Supplementary Methods file 10. Binary outcomes were summarized using the Risk Relative (RR) as a metric, whereas continuous outcomes were summarized as standardised mean difference (SMD).A Bayesian random-effects NMA based on the Markov chain Monte Carlo (MCMC) simulation from the posterior distribution was applied to estimate the relative effects. For binary outcomes, we used binomial likelihood and modeled the log relative risk directly. For continuous outcomes, we used the normal likelihood and the identity link. Given the head-to-head comparisons , we assumed non-informative but biologically plausible priors for treatment effects. Details of model fitting, model diagnostics, and estimation methods are presented in Supplementary Methods file 11.We presented summary treatment effect estimates and between-trial variance derived from the median and corresponding 95% credible intervals (CrIs) from the 2.5th and 97.5th percentile of the posterior distribution.2 across comparisons in both NMA and inconsistency models. We contrasted the posterior summaries and deviance information criteria (DIC) of the inconsistency and consistency models28.Bayesian pairwise meta-analysis (direct evidence) was performed to assess the consistency of NMA. As treatments included in each network of trials have inherent variability, we assumed common τAs a sensitivity analysis, we performed a consistency model of NMA within a frequentist approach and using fixed-effects models. For continuous outcomes, we used the inverse-variance model. For safety or immunogenicity outcomes, we used the Mantel–Haenszel method. The results were summarized with 95% Confidence Intervals (CI).We performed subgroup analyses by type of reference molecule  for all efficacy outcomes.We performed a visual inspection of comparison-adjusted funnel plots for each outcome (≥ 10 studies) to investigate the association between trial size (precision) and treatment effects. Comparison-adjusted funnel plots were considered symmetrical when about the zero line there were no small-sample effects present.We used Stata 16.0. and WinBUGS software . Network plots were generated using Stata 16.0.20. The observation that 95% CrIs fall entirely to two sides of the margins of equivalence defines equivalence20. For the ACR20 outcome, we assumed an equivalence margin on the relative risk of . For the HAQ-DI outcome, the equivalence margin on SMD units was . Thus, the probability of equivalence was defined as the proportion of Markov Chain Monte Carlo simulations in which the random-effects summary estimate was contained within the equivalence margins.We estimated the posterior probabilities of equivalence for the primary (ACR20) and co-primary (HAQ-DI) outcomes using prespecified margins of equivalence computed from large placebo-controlled trials and endorsed by experienced rheumatologists30.The Grading of Recommendations Assessment, Development and Evaluation (GRADE) 4-step approach was used for rating the quality of effect estimates from the NMA of each outcome (Supplementary Methods file 12)70 assessed equivalence with at least one switching phase. Among these, three trials had a subsequent-second switching phase   Fig. d. There In total, 17 trials provided data on 6,562 patients with moderate to severe rheumatoid arthritis with previous use of methotrexate. The median of participants per arm was 120 (IQR: 123–204)  Efficacy; 2) Safety, and 3) Immunogenicity outcomes. For each category of the outcome, the results are presented as follows: (a) The network evidence plot of eligible trials for all outcomes Figs. –S6; (b)  Safety,  ImmunogeFigure 2 = 0.0) for all efficacy outcomes. Similar findings in the direction of the null effect are expected in future exchangeable studies (Table Table es Table .2 = 0.0). The 95% Bayesian CrIs for three pair-wise comparisons were entirely contained within the [0.94 to 1.06] prespecified equivalence margins. The effect estimates for other comparisons involving the switching arm (Bios-Ref) were less imprecision because there was only one study, but still compatible with the hypothesis of equivalence. The posterior probability of equivalence varies from 61.4 to 99.8% with the lowest probability in comparisons with Bios-Ref . For this comparison, the posterior probability of equivalence was 96.4%. For the other comparisons, there is a lower probability of equivalence because only one trial assessed the non-switching arm Ref-Ref, and CrIs crossed the bounds of the equivalence margin  and the prevention of structural damage progression (mTRSS) Tables . We did The results of subgroup analysis by type of TNFIs molecule are consistent but less precise when compared with all TNFIs pooled together and with higher heterogeneity between trials. Overall, the multi-arms trials from adalimumab contributed more to the network evidence, followed by infliximab, and least, etanercept Table .The Bayesian NMA for the overall TEAE and discontinuation rates included 15 switching trials involving more than 6400 patients and four nodes Fig. . The eviThe Bayesian NMA for the risk of ADAs included 16 switching trials, 6,006 patients, and four nodes Fig. . The immBy contrasting the inconsistency and consistency models, we did not find any evidence of inconsistency in summary effect estimates Table . The absThe results were comparable, and all conclusions are unchanged using Frequentist fixed-effect approach for NMA, which did not consider heterogeneity between the studies Tables  to S13.We found suspected asymmetry in the comparison-adjusted funnel plots for ACR20, ACR50, ACR70, and serious TEAE, suggesting a higher probability of publication bias Figs. , and S10There was low to moderate certainty that switching between biologics and biosimilars of TNFIs results in little to no differences in effects on efficacy when compared to those continuing the original treatments. There was moderate certainty that the switching arm (Ref-Bios) had similar rates of TEAE compared to the non-switching arms. There was low to moderate certainty that rates of discontinuation and formation of ADAs and Nabs were similar within or between switching and non-switching arms. There was very low certainty about the impact of switching on the risk of serious TEAE, and special adverse of interest due to a low number of events and high heterogeneity between trials Table .To the best of our knowledge, this is the most comprehensive systematic review and NMA within a Bayesian framework to evaluate the impact of switching between biosimilars of adalimumab, etanercept, and infliximab and its reference biologics drugs on rheumatoid arthritis treatment. Data were obtained from 17 switching trials including 6,562 patients with moderate to severe rheumatoid arthritis. Overall, the evidence from the NMA showed that neither efficacy, safety, nor immunogenicity was affected by switching. Although the precision of safety and immunogenicity findings was limited, the duration of follow-up may be inadequate for a comprehensive assessment of long-term effects, particularly concerning malignancy risks.We would like to highlight the main findings from our NMA. First, the clinical response or functional capacity of patients after switching was equivalent within and between switching and non-switching groups, and all comparisons met prespecified margins of equivalence. Second, there is evidence of a similar risk of experiencing TEAE or discontinuing study rates i.e., comparable safety and tolerability were observed after switching. Given the rare rates of some adverse events, however, we are uncertain about the effects of switching in these cases. Third, the immune response was comparable for patients in both switching and non-switching treatment arms.18 providing together enough evidence to support switching between reference biologics and biosimilars of TNFIs in patients with rheumatoid arthritis. This conclusion is in line with publications of the main medical societies of rheumatoid arthritis supporting the single switch from a reference biologic to an approved biosimilar in clinical practice7. In the opposite line, Numan and Faccin15 showed that the evidence from 98 switching studies was inconclusive and inconsistent, including 10 randomized trials and 30 real-world studies involving rheumatoid arthritis populations. The authors argued that included studies had divergent rates of discontinuation and a lack of key design elements for assessing switching. In our study, there was evidence of similar discontinuation rates between patients who switched treatments and those who continued the original treatment. Although we extended the finding that these trials were at high risk of bias, new studies should attempt to incorporate essential aspects of quality and reporting when assessing the impact of switching between treatments.The robust findings from our NMA add to the other systematic reviews8.Our study provides novel evidence regarding switching from a biosimilar to a reference, i.e., switching back to the original treatment as being an efficacious and safe practice. Even though, the confidence of the effects estimates for this type of switch was limited by the low number of trials available. Of note, our evidence does not address the issue of switching from a biosimilar to another biosimilar of the same reference biologic drugs or switching multiple times. These questions remained to be answered and should be the object of future researchProper interpretation of the results of our NMA requires consideration of some of its features and limitations. First, several comparisons such as those involving the switching arm (Bios-Ref) included only one or few studies, limiting the confidence of estimates. Second, special attention should be given to the interpretation of some safety and immunogenicity outcomes, which indicated the null effect between switching and non-switching arms. The switching phase duration varied between trials, and for some outcomes such as serious infections, data were sparse (low rates of events and wide CrIs) with high heterogeneity between studies. Third, we included trials from three different molecules of the same drug class, so possibly we could not detect differences inherent to each molecule. Indeed, we did not observe any systematic differences in the main demographic and clinical characteristics of the populations analyzed. Also, we did not identify any systematic differences across trials since we included RCT of equivalence followed by a switching phase. We did not find any inconsistency between the consistency (NMA) and inconsistency model (direct evidence). Furthermore, our subgroup and sensitive analysis showed consistent results with the main analysis. Finally, this study assessed only the impact of the first switching after 6 months after re-randomization or after the open-label extension, and we cannot infer from our results a decision to a multiple switching context or long-term effects of switching.Our Bayesian NMA provided compelling evidence that switching treatments, either from a reference biologic to a biosimilar or from a biosimilar to a reference biologic of TNFIs did not impact significantly the clinical, safety, and immunogenicity responses when compared to non-switching treatments. Although safety results were imprecise and the follow-up period might not be sufficient to evaluate long-term effects, mainly regarding malignancies. Nonetheless, these findings support the rational practice of switching reference biologics and biosimilar drugs of adalimumab, etanercept, and infliximab for patients with rheumatoid arthritis.Supplementary Information.