How to Anticipate Public Health Indicators Using Wastewater SARS-CoV-2 Concentration During the COVID-19 Pandemic. Madrid Region Case Study

This study analyzes the presence and dynamics of SARS-CoV-2 in sewage sanitation systems in the Madrid region. The statistical results and data generated are presented daily via a platform as a tool for the early detection of SARS-CoV-2 and its spread based on the WBE (wastewater-based epidemiological) approach. The number of sampled points amounts to a total of 289 sampling points in terms of SARS-CoV-2 concentration that collects over six million and a half inhabitants’ discharges. The project was developed by Canal de Isabel II, the water utility company from Madrid. The research evaluates the correlation found between SARS-CoV-2 concentration in wastewater and the following public health indicators: incidence rate, reported active cases and COVID-19 hospitalization data (regular hospitalization and ICU admission cases).SARS-CoV-2 presence and dynamics in wastewater show a strong connection with both 14-day incidence rates with active infection and reported COVID-19 hospitalizations. A lag varying from 3 to 8 days between wastewater presence and hospitalizations is explained because the infection is found in the feces of patients before symptom onset. The resulting data are available for consultancy on the company’s website (named VIGÍA project) as well as on the regional government’s websites.The results have already been useful to anticipate the second and third COVID-19 waves in Madrid. Information is shared daily with health authorities for consultancy and decision-making. The results are available as an aggregation for the entire region and for each sewershed.

Strict Adherence to Anti-Epidemic Measures Prevents ICU Staff from SARS-Cov2 Infection

During the first wave of the SARS Cov-2 virus pandemic, we faced a rapidly spreading infection in the Czech Republic. The lack of experience with a pandemic of such magnitude and the inconsistent information on the situation in China and Italy meant that we were forced to introduce an effective anti-epidemic measures in a very short period to protect our patients. One of the key measures that significantly contributed to the successful management of the first wave of the pandemic was to prevent the spread among healthcare professionals who directly cared for patients with active infection. During and after the first wave of the pandemic, we conducted a local observational study to assess the infection rate in ICU health care professionals who were in direct contact with infected patients. We believe that the successful management of the first wave of the pandemic and the experience gained by the entire team will help to manage the further course of this pandemic as well as other epidemics in the future. Here we bring our own experience from University Hospital ICU, which was selected to treat critically ill Covid-19 positive patients from whole region.

First detection of SARS-CoV-2 B.1.617.2 (Delta) variant of concern in a symptomatic cat in Spain

Natural and experimental SARS-CoV-2 infection in pets has been widely evidenced since the beginning of the COVID-19 pandemic. Among the numerous affected animals, cats are one of the most susceptible species. However, little is known about viral pathogenicity and transmissibility in the case of variants of concern (VOCs) in animal hosts, such as the B.1.617.2 (Delta) variant first detected in India. Here, we have identified the B.1.617.2 (Delta) VOC in a cat living with a COVID-19 positive owner. The animal presented mild symptoms (sneezing) and a high viral load was detected in the oropharyngeal swab, suggesting that an active infection was occurring in the upper respiratory tract of the cat. Transmission from the owner to the cat occurred despite the human being fully vaccinated against SARS-CoV-2. This study documents the first detection of B.1.165.2 VOC in a cat worldwide and emphasizes the importance of performing active surveillance and genomic investigation on infected animals.

Role of Extra-anatomic Ascending to Descending Bypass in Complex Thoracic Aortic Pathology

Complex pathology of the distal arch and proximal descending thoracic aorta is usually approached by stent endografting or in situ graft replacement. Oftentimes, these options are not feasible due to unfavorable anatomy, multiple previous procedures, active infection, or presence of concomitant cardiac disease. Thoracic aortic extra-anatomic bypass, as part of an open surgical strategy, is a useful and often the only curative option left for the treatment in these patients. Herein, we describe two cases that illustrate the utility of extra-anatomic thoracic aortic bypass for complex aortic disease.

A SARS-CoV-2 antigen rapid diagnostic test for resource limited settings

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19 disease. RT-qPCR has been the primary method of diagnosis; however, the required infrastructure is lacking in many developing countries and the virus has remained a global challenge. More inexpensive and immediate test methods are required to facilitate local, regional, and national management strategies to re-open world economies. Here we have developed a SARS-CoV-2 antigen test in an inexpensive lateral flow format to generate a chromatographic result identifying the presence of the SARS-CoV-2 antigen, and thus an active infection, within a patient anterior nares swab sample. Our 15-min test requires no equipment or laboratory infrastructure to administer with a limit of detection of 2.0 × 102 TCID50/mL and 87.5% sensitivity, 100% specificity when tested against 40 known positive and 40 known negative patient samples established by a validated RT-qPCR test.

The Dynamics of Hepatic Fibrosis Related to Schistosomiasis and Its Risk Factors in a Cohort of China

China has had a long history against schistosomiasis japonica. The most serious prognosis of chronic schistosome infection is hepatic fibrosis, which develops into advanced schistosomiasis if the process is not effectively controlled. After a more than seven decades endeavor, China has gained remarkable achievements in schistosomiasis control and achieved transmission control nationwide (infection rate of schistosomes in residents and domestic animals both less than 1%) by 2015. However, new advanced schistosomiasis cases emerge annually in China, even in areas where the transmission of schistosomiasis had been interrupted. In the present study, the residents (>5 years old) in a schistosomiasis endemic village were examined for schistosomiasis every year during 1995–2019 by the modified Kato–Katz thick smear method and/or miracidium hatching technique. Residents who were identified to have an active infection method were treated with praziquantel at a dose of 40 mg/kg body weight. Ultrasonography was carried out to assess the liver morbidity related to schistosomiasis in 1995 and 2019, respectively. The prevalence of schistosomiasis among residents presented a downward trend annually, from 17.89% (175/978) in 1995 to 0 (0/475) in 2019. Among 292 residents who received ultrasound scan both in 1995 and 2019, 141 (48.29%) presented stable liver damage, while liver fibrosis was developed severely in 86 (29.45%) and reversed in 65 (22.26%) residents. Univariate and multivariate analysis showed that anti-fibrosis treatment was the protective factor against schistosomiasis hepatic fibrosis. Males, residents aged 38 and above, fishermen, and people who did not receive anti-fibrosis treatment were groups with higher risk of liver fibrosis development. Our results revealed that although the infection rate of schistosome dropped significantly in endemic areas, liver fibrosis was still developing among some residents, even though they had received deworming treatment. Liver protection/anti-fibrosis treatment should be administered in endemic regions and regions with historically uncontrolled transmission to slow down the deterioration of hepatic fibrosis among patients in schistosomiasis endemic areas.

Longitudinal Transcriptional Analysis of Peripheral Blood Leukocytes in COVID Convalescent Donors

Abstract Introduction Severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) can induce a strong host immune response. Several groups have investigated the course of antibody responses in patients recovering from SARS-CoV-2 infections but little is known about the recovery of cellular immunity. This study investigated the cellular immune response in people who had recovered from SARS-CoV2 infection. Methods 162 coronavirus disease 2019 (COVID-19) convalescent plasma donors (CCD) and 40 healthy donor (HD) controls were enrolled prospectively in an IRB-approved protocol (Clinical Trials Number: NCT04360278) and provided written informed consent to participate in the study. Using the nCounter platform and host response panel with 785 genes across more than 50 pathways, we compared transcriptomic profiles on RNA samples obtained from the peripheral blood leukocytes of these 162 CCD and 40 HD. Additionally, in 69 of the 162 CCD samples, we evaluated transcriptomic trends at more than one-time point during the convalescent period. Results Age, sex, ethnicity, and body mass index distributions were similar among the CCD and HD. With respect to baseline complete blood counts, hemoglobin, platelets, and absolute basophil and eosinophil counts, all were similar among CCD and HD (Table 1). However, despite sample collections occurring several days after convalescence, mean counts for absolute neutrophil counts, absolute monocyte counts, and absolute lymphocyte counts were significantly higher among CCD compared to HD. 30-90 days after diagnosis, 19 of 773 genes differed (FDR < 0.05) between the average CCD and HD samples. Up-regulated genes included MAFB, CTLA4, PTGS2, and the chemokine signaling genes CXCR4, CXCL5, CXCL2 and CCR4. Down-regulated genes included PTGER2, CASP8, and the interleukins IL36A, IL31, IL20 and IL21 (Figure 1 a,b). Differential gene expression persisted for months. At 90-120 days, 13 genes were differentially regulated, including again MAFB CXCR4, PTGS2, CXCL2 and PTGER2, plus SMAD4. At 120-150 days post-diagnosis, 58 genes were differentially expressed (FDR < 0.05) compared to HD. Pathways with up-regulated genes included Treg differentiation, type III interferon signaling and chemokine signaling. 150-360 days post-diagnosis, 4 genes remained up-regulated on average (FDR < 0.05): PTGS2, PIK3CR, CXCL1 and SMAD4 (Figure 1 c,d). Individual patients varied considerably from the mean trend. Scoring samples by their similarity to the gene expression profile of the mean HD sample, 21 CCD samples from 20 unique patients (12%) were identified as highly perturbed from HD. 84% of these highly perturbed samples were collected > 90 days post-diagnosis. Of these 21 samples, 6 were distinguished by > 2-fold up-regulation of a cluster of interleukin and type-1 interferon genes (Figure 2). Conclusions Overall, our study identified important gene expression trends in CCD compared to HD in the post-acute period. The changes varied with time and among donors. As the expression of T-cell inhibitory molecule CTLA4 fell, the number of differentially expressed increased with the most marked changes occurring 120 to 150 days post-diagnosis in genes in chemokine signaling, type III interferon signaling and Treg pathways. Persistent alterations in inflammatory pathways and T-cell activation/exhaustion markers for months after active infection may help shed light on the pathophysiology of a prolonged post-viral syndrome observed in individuals following recovery from COVID-19 infection. Our data may serve as the basis for risk modification strategies in the period of active infection. Future studies may inform the ability to identify druggable targets involving these pathways to mitigate the long-term effects of COVID-19 infection. Figure 1 Figure 1. Disclosures Danaher: NanoString Technologies: Current Employment, Current holder of individual stocks in a privately-held company.

Outcomes of Haploidentical Salvage Transplantation Using Post-Transplant Cyclophosphamide for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy. Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis. Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21). Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. Figure 1 Figure 1. Disclosures Nakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

Safety and Short-Term Efficacy of Venetoclax Combined with Azacitidine in Acute Myeloid Leukemia: A Single Institution Experience

Introduction The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor (venetoclax) combined with hypomethylating agents (azacitidine) has shown promising activity in patients with acute myeloid leukemia (AML). However, there are no single center real-world research results with relatively large sample size in China. The purpose of this study is to explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven + AZA) in previously untreated patients who were ineligible for standard chemotherapy and patients with relapsed/refractory (R/R) AML in China. Methods A retrospective study was conducted on 60 previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML who received Ven + AZA (venetoclax，100mg D1、200mg D2、400mg D3-28；azacitidine, 75mg/m2 D1-7) in the Peking University Institute of Hematology from March 15, 2019 to May 20, 2021. The incidence of adverse events (AE), complete remission (CR)/CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) and minimal residual disease (MRD) status in patients with different risk stratification and different gene subtypes were analyzed. Results Patient Characteristics The median age was 54 (18-77) years, 33 males (55.0%), and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients who were ineligible for standard chemotherapy and 36 (60.0%) were R/R patients. The median cycles of Ven + AZA in the two groups were both 1 (1-5). The median follow-up time of them were 2.9 (1.5-13.2) and 118 (1.4-26.3) months, respectively. In the previously untreated patients who were ineligible for standard chemotherapy, 2 were over 75 years old, 16 cases were diagnosed with active infection, 6 had organ dysfunction. According to the risk stratification of NCCN, it was divided into 8 cases of favorable-risk, 2 cases of intermediate-risk and 14 cases of poor-risk. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 cases in the poor-risk group (CR to hematological recurrence <18 months, no remission after 1 cycle of therapy, no remission after ≥2 cycles of therapy). Efficacy In the previously untreated patients who were ineligible for standard chemotherapy, after the first cycle of Ven + AZA treatment, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) cases achieved partial remission (PR), and the ORR was 83.3%. Among the CR/CRi patients, 8/17 (47.1%) achieved MRD negative after 2 cycles of therapy. Four patients achieved CR/CRi after the first cycle of Ven + AZA, ineligible factors (active infection) were eliminated, followed by chemotherapy, and MRD achieved negative after 1-2 cycles of consolidation therapy. The median duration of induction therapy in R/R group was 28 (14-28) days, and the total CR/CRi rate was 58.3%. 11/24 (45.8%) cases achieved CR/CRi after one cycle of Ven + AZA in the poor-risk R/R group, and 10/12 (83.3%) cases achieved CR/CRi in the favorable-risk R/R group, which was significantly superior than that in the poor-risk group (P = 0.031). The efficacy in patients with different risk stratification and gene subtypes are displayed in Table. Safety The incidence of hematological AEs was 100%, and the incidence of neutropenic fever was 40.0% (24/60). The incidence of grade 3-4 leukopenia was 86.7% (52/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 leukopenia caused by therapy was 26.7% (16/60). The incidence of grade 3-4 anemia was 71.7% (43/60), of which 51.7% (31/60) occurred before therapy, and the incidence of grade 3-4 anemia caused by therapy was 20.0% (12/60). The incidence of grade 3-4 thrombocytopenia was 76.7% (46/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 thrombocytopenia caused by therapy was 16.7%. The most common non hematological AE was infection, followed by gastrointestinal AE. Infection mainly included pneumonia (13.3%) and soft tissue infection (6.7%), both of which were grade 3-4. Conclusion Ven + AZA has acceptable safety in previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML, can achieve a high response rate, and some patients can achieve MRD negative in China. It is effective in patients with NPM1, IDH1/IDH2 and TP53 positive. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.