Correlation between levels of anti-cytokine antibodies, recombination activity of the mutant RAG proteins and clinical phenotype in patients with RAG deficiency

RAG mutations cause various phenotypes: SCID, Omenn syndrome (OS), leaky SCID (LS) and combined immunodeficiency (CID). We had previously reported autoantibodies targeting IFN-alpha, IFN-omega in patients with RAG deficiency. However, how the presence of such antibodies correlated with the severity of the clinical phenotype and with the recombination activity of the mutant proteins was unknown. To address this, we have studied anti-cytokine antibodies in 118 patients with RAG defects (SCID, n = 28;OS, n = 29;LS, n = 29;CID, n = 32), and in 42 controls (protocols NCT03394053 and NCT03610802). RAG mutant proteins associated with CID and LS retained 35.6 +/- 4.3 (mean +/- SE) and 29.8 +/- 5.1% recombination activity respectively, compared to wildtype protein, which was significantly higher than the recombination activity of the mutant RAG proteins associated with OS (4.1 +/- 1.5%) and SCID (5.7 +/- 2.1%) (p < 0.0001). Among 32 CID patients, 24 tested positive for anti-IFN-alpha and 21 for anti-IFN-omega antibodies. Among 29 LS patients, 15 had high levels of anti-IFN-alpha and 13 of anti-IFN-omega antibodies. A minority of the CID and LS patients had also high levels of anti-IFN-beta and anti-IL-22 antibodies. By contrast, none of the OS patients tested positive for anti-cytokine antibodies. High levels of anti-IFN-alpha and anti-IFN-omega antibodies correlated with their neutralizing activity as demonstrated in vitro by analysis of STAT1 phosphorylation upon stimulation of healthy donor monocytes in the presence of the appropriate cytokine and patient's or control plasma. Severe viral infections were recorded in 26/41 patients with CID and LS who tested positive and in 7/20 who tested negative for anti-IFN-alpha and/or anti-IFN-omega antibodies (p <0.05). Among those with anti-IFN antibodies, EBV (n = 8), CMV (n = 6), HSV (n = 5), VZV (n = 4) and adenovirus (n = 4) infections were more common. Two patients had COVID-19, which was fatal in one. Presence of the rubella virus was documented in 5 patients with anti-type I IFN antibodies. These results demonstrate that high levels of neutralizing anti-IFN-alpha and anti-IFN-omega antibodies are common in patients with RAG mutations manifesting as CID and LS, but not in those with OS, and that their presence is associated with a high risk of serious viral infections.Copyright © 2023 Elsevier Inc.

The Company You Keep: How Network Disciplinary Diversity Enhances the Productivity of Researchers

The Covid-19 pandemic has affected most organizations' working environment and productivity. Organizations have had to make arrangements for staff to operate remotely following the implementation of lockdown regulations around the world, as the pandemic has led to restrictions on movement and the temporary closure of workplace premises. The purpose of this paper is to gain a deeper understanding of the effect of this transition on productivity during the pandemic, by studying a distributed network of research who collaborate remotely. We examine how the productivity of researchers is affected by the distributed collaborative networks in which they are embedded. Our goal is to understand the effects of brokerage and closure on the researchers' publication rate, which is interpreted as an indicator of their productivity. We analyze researchers' communication networks, focusing on structural holes and diversity. We take into account the individual qualities of the focal researcher such as seniority. We find that disciplinary diversity among researchers' peers increases the researchers' productivity, lending support to the brokerage argument. In addition, we find support for two statistical interaction effects. First, structural holes moderate diversity so that researchers with diverse networks are more productive when their networks also have a less redundant structure. Diversity and structural holes, when combined, further researchers' productivity. Second, seniority moderates diversity such that senior researchers are more productive than junior researchers in less diverse networks. In more diverse networks, junior researchers perform as well as senior researchers. Social capital and human capital are complementary. We conclude that the benefits of diversity on researchers' productivity are contingent on the qualities of the researchers and on network structure. The brokerage/closure debate thus needs a more nuanced understanding of causal relationships. © 2022 SAGE Publications.

Impact of COVID-19 on gynaecological patient care: results of patient's survey with 327 patients.

PURPOSE: The pandemic SARS-CoV-2 poses new and unprecedented challenges for health care systems on a national and global level. Although the current situation has been going on for more than 1 year, there is limited data on the impact of the pandemic on general hospital and medical practice care. This survey captures the perspective of patients with gynaecological diseases of this impact. METHODS: Using a paper-based questionnaire, 327 patients were asked about medical care and their experiences during the pandemic at the University Hospital Bonn and the University Hospital Charité Berlin. The study was performed from the 1st June to 30th September 2020. RESULTS: A total of 327 patients participated in the study: 156 stated to have been tested for coronavirus, and 1 patient reported a positive test. 41.3% of the patients felt insecure about the current situation, 30.4% were concerned about the risk of infection during the hospital stay. The pandemic-specific measures in hospitals and medical practices unsettled 6.8% of patients. 18.1% of patients feared that their gynaecological disease would not be treated adequately due to the pandemic. 55.7% of patients reported that their confidence in their physicians has increased during the pandemic. CONCLUSION: The results show that patients' confidence in the healthcare system and the physicians acting significantly increased during the COVID-19 crisis. Transparent and comprehensive information policy regarding actions and restrictions within the COVID-19 crisis eases patients concerns and improves patients' confidence in their physicians, which is crucial for a successful treatment's outcome.

Implications of the COVID-19 pandemic: results of a German survey on patient care and clinical trials in gynecological oncology (MONITOR-17 Survey)

Introduction/Background*This survey describes the German-wide impact of the COVID-19 pandemic on provision of clinical care and recruitment in clinical trials of patients with gynecologic malignancies from a physician’s perspective.MethodologyWe performed an online anonymous multicentric prospective survey across clinicians in Germany. The multiple-choice questionnaire was administered at 4-6 weekly intervals from April 2020 to October 2020 for a total of four series.Result(s)*483 questionnaires were completed. The majority of participants were gynecological oncologists (83.3%) in certified gynecologic cancer centers (61%) and breast cancer (BC) centers (80.4%). The majority stated a 50% reduction in surgical interventions for gyne-oncological cases. Cases that were prioritized for surgery across all tumors were those with early stage disease, at primary situation and with a good ECOG status. For BC, patients following neoadjuvant chemotherapy treatment and those with high-risk or locally-advanced BC were prioritized. The majority (73%) continued to conduct clinical trials throughout the pandemic. In cases were trials were discontinued, this decision was made by sponsors, and hospital officers. Other reasons for discontinuation included lack of patient-participation (due to fear of attending appointments). Almost 100% of the responders refuted any increased tendency to treat with a neoadjuvant approach (cytotoxic, hormonal, radiation) patients that would qualify for surgery under normal circumstances . This comes in direct contrast to the increased attitude to treat with neoadjuvant anticancer therapy of advanced cancers in other European countries.Only 18% of the clinicians reported feeling adequately informed about established safety pathways for COVID-19 positive patients with gynecological cancers. More than 43% of the clinicians felt that the COVID-19 pandemic will continue to impact on clinical care for up to 2 years.Conclusion*Targeted emergency algorithms for patients with gynecological cancers need to be developed to protect and preserve care and treatment options for our patients in future pandemics.

Patient care and clinical trials in gynecological oncology: Implications of the COVID-19 pandemic

Background: This is a prospective international Survey to evaluate the impact of the COVID-19 Pandemic on the management of patients with gynecological malignancies from the multidisciplinary physicians' perspective, with particular focus on clincial infrastructures, and trial participation. Methods: The anonymous online survey consisted of 53 COVID-related questions. It was sent to all healthcare professionals in gynaecological oncology centres across Europe and the Pan-Arabian region from April 2020 to October 2020. All healthcare professionals treating women with gynecological cancers were able to participate in the survey. Results: A total of 243 answers were collected from 30 different countries. The majority (73%) of participants were gynecological oncologists from university hospitals(71%) with at least an Intensive care unit with cardiopulmonary support available at their institutions. Most institutions continued to perform elective surgeries only for oncological cases (98%). Patients had to wait on average 2 weeks longer for their surgery appointments compared to previous years(range 0-12 weeks). Cases that were prioritised for surgical intervention across all tumors (Ovarian, Endometrium, Cervical) were early stage disease (74%), primary situation (61%), and good ECOG status (63%). The radicality of surgery did not change in the majority of cases (78%) across all tumor types. During the pandemic, only 38% of clinicians stated they would start a new clinical trial. 45% stated the pandemic has negatively impacted the financial structure and support for clinical trials. 79% do not routinely screen patients included in trials for SARS CoV2. Overall, approx. 20% of clinicians did not feel well informed regarding clinical pathways for COVID-19 patients throughout the pandemic. The majority preferred regular updates and training via Webinars (75%), followed by tumorboards and interdisciplinary conferences (45%). 30% of clinicians stated that they are currently experiencing difficulties in providing adequate medical care due to staff shortage. Conclusions: Despite well-established guidelines for patient care and performing clinical trials in gynecological oncology, the COVID-19 pandemic has impacted clinical research, and financial structures. Longer waiting times for operative interventions, less support for clinical trials and concerns regarding provision of adequate medical care and triaging patients are very real. This survey underlines the necessity for building robust emergency algorithms tailored to gynecological oncology patients in the future.