Antibody Response and Molecular Graft Surveillance in Kidney Transplant Recipients Following Sars-CoV-2 Vaccination

Purpose: Preliminary studies suggest that kidney transplant recipients (KTRs) show diminished humoral responses to SARS-CoV-2 vaccination. Although reports of allograft rejection after SARS-CoV-2 vaccination have been rare, there is no recommended framework for monitoring for potential vaccine-related allograft injury. Here, we describe an approach for longitudinal assessment of immunogenicity and safety of SARS-COV-2 vaccination in KTRs. Method(s): KTRs eligible for SARS-CoV-2 vaccination were identified through medical records, beginning March 12, 2021. Baseline and weekly blood samples were collected for SARS-CoV-2 spike protein antibody titers, dd-cfDNA and gene expression profiling (GEP) for 12 weeks. Donor specific antibody (DSA) testing was performed at baseline, 2 weeks after completion of vaccine doses and at week 12. Antibody response was defined as a 10-fold increase in total binding IgG titers. Result(s): 49 KTRs were identified for analysis. Patient demographics are shown in Table 1. Ten patients (20.4%) demonstrated a spike antibody response post- vaccination. Of responders, 80% (n=8) had a history of COVID-19. The odds ratio for the association of a history of COVID-19 with vaccine response was 18.3 (95% CI 3.2, 105.0, p=0.0005). Median dd-cfDNA levels did not differ between pre- and postvaccination (0.23% versus 0.21% respectively). There was no significant difference between pre- and post-vaccination GEP scores (9.85 versus 10.4 respectively). No patients developed clinically significant DSA, eGFR decline or allograft rejection following vaccination. Conclusion(s): Quantitative antibody responses were strongly associated with a diagnosis of prior SARS-CoV-2 infection. Stability of eGFR, dd-cfDNA, GEP profiles and lack of allosensitization reinforce the safety profile of SARS-CoV-2 vaccination in KTRs. Further studies are needed to better understand immunogenicity in SARSCoV- 2 naive individuals, including whether cellular responses are protective in the absence of humoral responses.

Antibody Response and Cellular Phenotyping in Kidney Transplant Recipients Following Sars-CoV-2 Vaccination

Purpose: Correlates of protection for SARS-CoV-2 vaccines are not well-established in kidney transplant recipients(KTRs). Studies have highlighted the importance of neutralizing antibodies(Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity, T and B cell response in KTRs following SARS-CoV-2 vaccination. Method(s): KTRs eligible for SARS-CoV-2 vaccination from 3/12/21 were enrolled. Baseline and weekly blood samples were collected for routine lab, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells post-vaccination. Result(s): 49 KTRs were enrolled ( Demographics -Table 1). 10 patients (20.4%) mounted an Ab response following vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV- 2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Fig 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naive participants (P = 0.09 for SARS-CoV-2-naive, P=0.03 for SARS-CoV-2-experienced adults, Fig 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naive patients only (Fig 1A-D). Conclusion(s): Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients irrespective of history of COVID-19. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigenspecific or confer immunity. (Table Presented).

A RETROSPECTIVE REVIEW OF 'MISSED' OESOPHAGEAL/GASTRIC CANCER DIAGNOSES AT MACCLESFIELD DISTRICT GENERAL HOSPITAL (MDGH)

Introduction There are approximately 15,000 new diagnoses of oesophageal and gastric cancer every year, in the UK (Cancer Research UK, 2022). Timely detection of cancer remains a key marker in prognosis and success of disease outcomes. Upper GI cancers diagnosed within 36 months of a previous oesophago-gastro-duodenoscopy (OGD) are defined as 'missed' cancer diagnoses. The British Society of Gastroenterology (BSG) states the acceptable rate of missed cancers is 10% or less (Beg S et al., 2017). Methods Retrospective case audit of 71 patients (6 patients excluded, 65 patients analysed), derived from the Somerset database, split into two cohorts of 2019-20 (pre- COVID-19 pandemic) and 2020-21 (during pandemic). Patient demographics, endoscopic, radiological and pathology reports of those diagnosed with oesophageal and gastric cancers were analysed. The number of endoscopies in the preceding 36 months were audited against BSG guidelines, to determine 'missed' cancer diagnoses. Results There were 47 male patients and 18 female patients in the cohort. The average age of patients (in years) diagnosed with oesophageal/gastric cancers in this sample population was 71.6. The age range of the sample population ranged from 50 years to 94 years. Total number of oesophageal cancers diagnosed in 2019-20 and 2020-21 were 31 and 15, respectively. The total number of gastric cancers diagnosed in 2019-20 and 2020-21 were 14 and 5, respectively. The total population area served by the hospital is approximately 200,000 people. The proportion of patients diagnosed with oesophageal/gastric cancer, during the audit timescale, who had had an endoscopy in the preceding 36 months was 7.7%. Accounting for explained anomalies, the number of patients who were diagnosed with a post-OGD oesophageal/gastric cancer was below the nationally acceptable upper limit for 'missed' cancers (10%). Conclusions 1) There was a reduction in the number of diagnoses of oesophageal and gastric cancers during the pandemic period, compared to the pre-pandemic period 1) The 'missed' oesophageal and gastric cancer rate was below the national acceptable limit of 10% 2) The emphasis on quality of endoscopy, regular training, use of descriptive classifications, image capture, biopsy numbers and minimum examination time of at least 7 minutes should be adhered to, to continue to improve detection rates (Beg S et al., 2017) 3) Further evaluation with artificial intelligence-based technology for lesion recognition should be evaluated to consider further reduction in rates of 'missed' cancer.

DD-CFDNA can guide safe reintroduction of immunosuppression in kidney transplant recipients with Covid-19

Purpose: COVID-19 infection is associated with 25% mortality in kidney transplant recipients (KTRs). Reduction of anti-metabolite immunosuppressants during the acute COVID-19 illness is a common approach in managing KTRs. This potentially increases the risk of allograft rejection in the setting of reduced immunosuppression. The optimal timing for safe reintroduction of immunosuppression remains unclear. Here we describe a novel approach of incorporating dd-cfDNA to safely titrate immunosuppression in patients with COVID-19. Methods: KTRs were monitored prospectively with dd-cfDNA beginning at the time of COVID-19 diagnosis or on discharge from acute care. If dd-cfDNA<1%, antimetabolite dosing was increased by 25% every two weeks. If dd-cfDNA>1% or a rapid relative change from baseline, antimetabolites were reintroduced at full dose provided the patient remained symptom free from COVID-19. Results: 58 KTRs (including 1 PAK) with COVID-19 infection were monitored with dd-cfDNA at the time of or following this diagnosis from March 2020 to January 2021. Demographics and directed treatments are summarized in Table 1. Median dd-cfDNA levels remained stable during longitudinal surveillance following COVID-19 (Figure 1A). 3/58 patients with COVID-19 and dd-cfDNA results available developed biopsy-proven rejection. One developed rejection at the time of COVID-19 diagnosis with elevated dd-cfDNA. 2/58 developed rejection in the setting of delayed re-introduction of antimetabolites due to clinical concerns (Figure 1B), however one did not have elevated dd-cfDNA. 10% of patients (n=6) had accelerated reintroduction of anti-metabolites due to dd-cfDNA levels>1% or rapid deviation from baseline. None of these patients developed rejection in the following months and dd-cfDNA levels decreased after immunosuppression reintroduction. Standard reintroduction of anti-metabolites with dd-cfDNA <1% was achieved with no associated episodes of rejection. Conclusions: dd-cfDNA presents a feasible adjunctive biomarker to guide immunosuppression titration in KTRs with confirmed COVID-19 and avoid allograft rejection during a time of increased immunological risk.

Impacts of COVID-19 on Canadian Beekeeping: Survey Results and a Profitability Analysis.

To gauge the impact of COVID-19 on the Canadian beekeeping sector, we conducted a survey of over 200 beekeepers in the fall of 2020. Our survey results show Canadian beekeepers faced two major challenges: 1) disrupted importation of honey bees (Hymenoptera: Apidae) (queen and bulk bees) that maintain populations; and 2) disrupted arrival of temporary foreign workers (TFWs). Disruptions in the arrival of bees and labor resulted in fewer colonies and less colony management, culminating in higher costs and lower productivity. Using the survey data, we develop a profitability analysis to estimate the impact of these disruptions on colony profit. Our results suggest that a disruption in either foreign worker or bee arrival allows beekeepers to compensate and while colony profits are lower, they remain positive. When both honey bee and foreign workers arrivals are disrupted for a beekeeper, even when the beekeeper experiences less significant colony health and cost impacts, a colony with a single pollination contract is no longer profitable, and a colony with two pollination contracts has significantly reduced profitability. As COVID-19 disruptions from 2020 and into 2021 become more significant to long-term colony health and more costly to a beekeeping operation, economic losses could threaten the industry's viability as well as the sustainability of pollination-dependent crop sectors across the country. The economic and agricultural impacts from the COVID-19 pandemic have exposed a vulnerability within Canada's beekeeping industry stemming from its dependency on imported labor and bees. Travel disruptions and border closures pose an ongoing threat to Canadian agriculture and apiculture in 2021 and highlight the need for Canada's beekeeping industry to strengthen domestic supply chains to minimize future risks.

Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma (AITL), is characterized by recurrent mutations affecting epigenetic regulators such as TET2, DNMT3A, IDH2 and RHOA. The association of aberrant DNA methylation with lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine, an epigenetic modifier which inhibits DNA methyltransferase, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the findings of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily was administered for 7 days prior to cycle 1 of CHOP, and for 14 days before CHOP cycles 2-6. Supportive care included mandatory G-CSF. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. Correlative biomarker studies are planned to assess genomic mutations by next-generation-sequencing (NGS), in addition to methylation and transcription profiles. Using a Simon two-stage design comparing an CR of ≥60% with treatment to an unacceptable CR of ≤35% (alpha=10%, power=80%), 9 or more CR out of 17 enrolled patients were required to declare the treatment worthy of further study. RESULTS: From 6/2018 to 3/2020, 21 subjects with previously untreated PTCL were enrolled at 4 centers, and the study met its accrual. At study entry, 17 patients (81%) had PTCL-TFH (16 AITL and 1 TFH), 3 with PTCL-NOS, 1 with ATLL, including 5 (24%) with CD30+ disease. The median age was 66 years (range 22-77), and the M:F ratio was 1.6:1. Nineteen (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (33%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (71.4%), thrombocytopenia (9.5%) and anemia (14.3%), with febrile neutropenia uncommon (14.3%). Grade 3-4 non-hematologic toxicities included fatigue (14.3%), hyponatremia (14.3%), diarrhea (4.8%), vomiting (4.8%), rash (4.8%), and elevated ALT (4.8%). One incidence each of influenza A, COVID-19 pneumonia, C.diff and strongyloides hyperinfection were observed and treated. There was no study treatment-related mortality to date. As of July 2020 at a median follow-up of 7 months (range 4-25 months), one subject withdrew consent after cycle 1 (patient preference), and 20 subjects had at least one response assessment, including 15 completed treatment, 2 progressed during treatment, and 3 nearing completion of therapy. At interim assessment after cycle 3 (n=20), the ORR was 85% with CR at 55% (90%CI of 34.7%-74.1%). To date, the preliminary end-of-treatment (EOT, n=17) CR was 76.5% (90%CI of 53.9%-91.5%) for all evaluable patients and was 86.7% for 15 PTCL-TFH, exceeding primary endpoint threshold. CR did not correlate with CD30 expression. The estimated 1-yr PFS for all patients was 56.8% (95%CI of 26.3%-87.3%), with 1-yrs PFS for PTCL-TFH at 61.1% (95%CI of 29.5%-92.7%), and the estimated 1-yr OS for all patients was 74.4% (95%CI of 48.8%-100.0%), with 1-yr OS for PTCL-TFH at 88.9% (95%CI of 68.4%-100.0%). Mutational status by NGS was determined in 15 patients to date. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 73%, 40%, 13% and 13%, respectively. TET2 mutations were significantly associated with CR (p=0.014), favorable PFS (p-0.012) and OS (p=0.042). In contrast, DNMT3A mutations were associated with adverse OS (p=0.028). CONCLUSIONS: This study provides the first demonstration that addition of hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is feasible, safe, and induces high CR rate in PTCL-TFH subtype, with expected side effects. Although preliminary, the EOT CR to date exceeds the threshold of meeting study primary endpoint. Final efficacy data as well as response according to subtype and mutational profiling will be updated at ASH. This active combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. [Formula presented] Disclosures: Ruan: Seattle Genetics: Research Funding;AstraZeneca: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Juno: Consultancy;BMS: Consultancy, Research Funding;Pharmacyclics: Research Funding;Kite Pharma: Consultancy. Moskowitz: Seattle Genetics: Research Funding;Incyte: Research Funding;Merck: Consultancy;Seattle Genetics: Consultancy;Bristol-Myers Squibb: Research Funding;Merck: Research Funding;Imbrium Therapeutics, L.P.: Consultancy;Miragen Therapeutics: Consultancy. Mehta-Shah: Bristol Myers-Squibb: Research Funding;Genetech: Research Funding;Innate Pharmaceuticals: Research Funding;Kyowa Kirin: Consultancy;Verastem: Research Funding;Karyopharm Therapeutics: Consultancy;Celgene: Research Funding;C4 Therapeutics: Consultancy. Sokol: EUSA Pharma: Consultancy, Honoraria, Speakers Bureau;Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees;Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees. Horwitz: Portola: Consultancy, Research Funding;Aileron: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Beigene: Consultancy;Daiichi Sankyo: Research Funding;C4 Therapeutics: Consultancy;ADCT Therapeutics: Consultancy, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Innate Pharma: Consultancy;Corvus: Consultancy;Trillium: Consultancy, Research Funding;Kyowa Hakka Kirin: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Mundipharma: Consultancy;Infinity/Verastem: Research Funding;Forty Seven: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Miragen: Consultancy;Myeloid Therapeutics: Consultancy;Verastem: Consultancy, Research Funding;Vividion Therapeutics: Consultancy;Affirmed: Consultancy;ASTEX: Consultancy;Janssen: Consultancy;Kura Oncology: Consultancy. Rutherford: LAM Therapeutics: Research Funding;Juno: Consultancy;AstraZeneca: Consultancy;Seattle Genetics: Consultancy;Genentech/Roche: Research Funding;Regeneron: Research Funding;Celgene: Consultancy;Heron: Consultancy;Karyopharm: Consultancy, Research Funding;Dova: Consultancy;Kite: Consultancy. Coleman: Novartis Pharmaceuticals: Research Funding;Innocare: Research Funding;Merck Sharp & Dohme Corp.: Research Funding;BeiGene: Research Funding;Acerta: Research Funding;Ipsen Group: Research Funding;BMS (Celgene Corporation): Research Funding;AstraZeneca Pharmaceuticals, LP: Research Funding;Karyopharma Therapeutics, Inc.: Research Funding;ARCUS Biosciences: Research Funding;AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding;Incyte Corporation: Research Funding;Eli Lilly and Company: Research Funding;EMD Serono Research and Development Institute Inc.: Research Funding;Genetech (F. Hoffman-LaRoche Ltd): Research Funding;Hutchinson MediPharma, LTD: Research Funding;Klus Pharma, Inc.: Research Funding;MeiPharma, Inc.: Research Funding;Seattle Genetics: Research Funding;Boston BIoMedical, Inc.: Research Funding. Melnick: Jubilant: Consultancy;Epizyme: Consultancy;Constellation: Consultancy;Janssen: Research Funding;Daiichi Sankyo: Research Funding. Cerchietti: BMS: Research Funding. Leonard: ADC Therapeutics: Consultancy;MEI Pharma: Consultancy;Bayer: Consultancy;Gilead/Kite: Consultancy;Karyopharm: Consultancy;GenMab: Consultancy;Regeneron: Consultancy;Sutro: Consultancy;AstraZeneca: Consultancy;Roche/Genentech: Consultancy;BMS/Celgene: Consultancy;Epizyme: Consultancy;Miltenyi: Consultancy. Martin: Regeneron: Consultancy;I-MAB: Consultancy;Sandoz: Consultancy;Janssen: Consultancy;Karyopharm: Consultancy, Research Funding;Teneobio: Consultancy;Bayer: Consultan y;Beigene: Consultancy;Cellectar: Consultancy;Incyte: Consultancy;Kite: Consultancy;Morphosys: Consultancy;Celgene: Consultancy. OffLabel Disclosure: Oral azacitidine (CC-486) as hypomethylating agent for the treatment of peripheral T-cell lymphoma

Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.

Real-time PCR assay as a simple and efficient tool for viral stability study.

Aim: For oncolytic virus trials, regulatory agencies often require pharmaceutical industry to evaluate risks of released viruses from patients to environment. This study was to establish a real-time PCR method to assess viral shedding and viral stability in human urine. Results/methodology: Herein, we describe an incubation of viral drug product in human urine and use of real-time PCR as a simple, efficient and high throughput assay to assess the level and stability of a nonenveloped and single stranded RNA virus. The viral stability issue is critical to the collection, transport, storage and testing of clinical samples. Discussion/conclusion: In summary, this simple method provides useful viral stability information at various temperatures and detergents. A similar approach may apply to other RNA viruses (including SARS-CoV-2).

Domestic violence in the coronavirus disease 2019 era: Insights from a survivor.

Amid the coronavirus disease 2019 (COVID-19) pandemic, there has been an alarming rise in domestic violence worldwide. Factors believed to be fueling this escalation in domestic violence include increasing social confinement at home during lockdowns and mounting stress levels from unemployment that have resulted from the economic uncertainties of these times. This contribution explores some of the challenges faced by physicians in clinically assessing victims of domestic violence during the COVID-19 era. One such challenge is the increased reliance on telemedicine during the pandemic, a medium of communication that offers a narrower clinical view of patients than is what is usually provided by an in-person examination. In this contribution, we offer suggestions on how best to screen for domestic violence, whether through telemedicine or during an in-person encounter. The history and physical findings that suggest domestic violence are reviewed along with recommendations on how to make the clinical examination more sensitive and compassionate to the needs of the victims. One of the authors of this contribution (L.C.H.) is herself a survivor of domestic violence and has courageously shared, in these pages, details of her harrowing near murder by an abusing husband. From this case history, it is hoped that readers will gain wider insights into what domestic violence means from the perspective of a victim and how we can better help save victims from this widespread and devastating social problem.

COVID-19-related skin manifestations: Update on therapy.

An increasing body of evidence has been produced in a very limited period to improve the understanding of skin involvement in the current coronavirus 2019 disease pandemic, and how this novel disease affects the management of dermatologic patients. A little explored area is represented by the therapeutic approach adopted for the different skin manifestations associated with the infection. An overview of the current scenario is provided, through review of the English-language literature published until October 30, 2020, and comparison with the personal experience of the authors. As dermatologists, our primary aim is to support patients with the highest standard of care and relieve suffering, even with lesions not life-threatening. With asymptomatic COVID-19 patients, patient discomfort related to skin lesions should not be undervalued and intervention to accelerate healing should be provided. Consensus protocols are warranted to assess the best skin-targeted treatments in COVID-19 patients.

Honey Bee Queen Production: Canadian Costing Case Study and Profitability Analysis.

The decline in managed honey bee (Hymenoptera: Apidae) colony health worldwide has had a significant impact on the beekeeping industry. To mitigate colony losses, beekeepers in Canada and around the world introduce queens into replacement colonies; however, Canada's short queen rearing season has historically limited the production of early season queens. As a result, Canadian beekeepers rely on the importation of foreign bees, particularly queens from warmer climates. Importing a large proportion of (often mal-adapted) queens each year creates a dependency on foreign bee sources, putting beekeeping, and pollination sectors at risk in the event of border closures, transportation issues, and other restrictions as is currently happening due to the 2020 Covid-19 pandemic. Although traditional Canadian queen production is unable to fully meet early season demand, increasing domestic queen production to meet mid- and later season demand would reduce Canada's dependency. As well, on-going studies exploring the potential for overwintering queens in Canada may offer a strategy to have early season domestic queens available. Increasing the local supply of queens could provide Canadian beekeepers, farmers, and consumers with a greater level of agricultural stability and food security. Our study is the first rigorous analysis of the economic feasibility of queen production. We present the costs of queen production for three Canadian operations over two years. Our results show that it can be profitable for a beekeeping operation in Canada to produce queen cells and mated queens and could be one viable strategy to increase the sustainability of the beekeeping industry.