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Background: Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 virus. Severity of this disease influenced by old age, sex, comorbidities, and other factors. Hypertension and type 2 diabetes mellitus are the most common comorbidities in COVID-19 patients that cause high morbidity and mortality. Objective(s): To analyze the survival of COVID-19 patients with hypertension comorbidity and compare it between diabetes mellitus and non-diabetes mellitus group. Method(s): This retrospective, descriptive study included COVID-19 patients with hypertension comorbidity at Internal Medicine ward Dr. Soetomo Hospital Surabaya from May 2020 to December 2021. Data on age, sex, hypertension, diabetes mellitus type 2, symptoms, vital signs, laboratory finding, length of stay, and outcome were taken from medical records and we carried out kaplan-meier method and log rank test by using SPSS. Result(s): This study obtained 698 sample of confirmed COVID-19 patients and after applying exclusion criteria there were 174 patients with hypertension comorbidity. Most patient were female (60.3%) and age 51-60 years (38.5%). The most common symptoms were shortness of breath (62.1%) and cough (50.6%). There were 50 hypertension and 79 non-hypertension patients died and Survival analysis showed a significant statistical difference between both groups (p=0.042). From 50 deceased hypertensive patients, there are 36 and 14 hypertensive patients with and without diabetes mellitus respectively but survival analysis showed a non-significant statistical difference between both groups (p=0.081) Conclusion(s): There is significant statistical difference in survival analysis in patients with hypertension. We should be aware about COVID-19 patients with hypertension.
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Background & Aim: Immune checkpoint inhibitors (ICI) revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Allocetra-OTS has an immune modulating effect on macrophages and dendritic cells and showed an excellent safety profile in patients including patients with sepsis and Covid-19. Here we investigated the anti-tumoral effect of Allocetra-OTS cellular therapy, in peritoneal solid tumor animal models. Methods, Results & Conclusion(s): Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis. Balb/c mice were inoculated intraperitoneally (IP) with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti- CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical score and weekly using IVIS (Fig.1). Kaplan-Meier log rank test was done for survival. For Allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis. Anti- CTLA4 standalone therapy significantly improved survival (Fig.2) from mean 34+/-9 to 44.9 +/-20 days. However, OTS standalone therapy was non-inferior and improved survival to 52.3 +/-20 days. Anti-CTLA4 + Allocetra-OTS combination therapy, ameliorated survival to 86.7+/-20 days with complete cancer remission in 60-100% of mice. Similar anti- tumoral effects of Allocetra-OTS were seen in mesothelioma model in a combination therapy with either anti-PD1 or cisplatin and using anti-PD1 in ID8 ovary cancer model. Based on single cell analysis confirmed by flow cytometry and pathology, the mechanism of action seems to be related or at least associated with an increase in f/480high peritoneal macrophages and a decrease in recruited macrophages, and to f/480high infiltration of the tumor. However, further studies are needed to confirm these observations. During IP tumor progression, Allocetra-OTS as a standalone therapy or in combination with ICI, or cisplatin, significantly reduced tumor size and resulted in complete remission in up to 100% treated mice. Similar results were obtained in ID8 ovary cancer. Based on excellent safety profile in > 50 patients treated in prior clinical trials for sepsis and Covid-19, Phase I/II clinical trial of Allocetra-OTS plus chemotherapy has started and three patient already recruited. A second phase I/II clinical trial of Allocetra- OTS plus anti-PD1, as a second- and third-line therapy in various cancers, was initiated in Q1 2023. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy
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Objectives: To describe the clinical characteristics and outcomes of SARSCoV-2 infection in patients with systemic vasculitis. Method(s): Observational, multicenter, cross-sectional analytical study in patients 18 or older diagnosed with systemic vasculitis with confirmed SARSCoV-2 infection (RT-PCR or serology) included in the SAR-COVID registry. Patients were evaluated from July 2020 to February 2022. Patients diagnosed with ANCA-associated vasculitis (AAV), other systemic vasculitides (Giant cell arteritis, Takayasu), and a control group of patients with other rheumatological diseases matched by age, sex, comorbidities, and date of SARS-CoV-2 infection. The survival curve of the groups was studied by Kaplan-Meier and compared through the Log-Rank Test. A Cox regression model will be performed to adjust survival for different variables (sex, age, treatments for underlying disease, treatments for viral infection, smoking, obesity, d-dimer level, and disease activity). Result(s): A total of 282 out of 2694 patients in the SAR-COVID registry were included, 57.4%women with a mean age of 55.7 years (SD 14.1). Fifty-four patients in the AAV group, 32 in the other vasculitis group, and 196 controls were studied. Hospitalization was required in 53.7% of the AAV group, 37.5% in other vasculitides, and 26.2% in the control group. 5.6% of patients in the control group presented acute respiratory distress syndrome (ARDS), 15.6% in the other vasculitis group, and 22.2% in the AAV group (p alpha 0.001). Complete recovery was observed in 82.3% of patients in the control group, 75%in the other vasculitis group, and 63%in the AAV group.We observed that 5.7% of the patients in the control group died from COVID-19, 9.4%from other vasculitides, and 27.8% in the AAV group (p alpha 0.001). We found a lower survival in the AAV group compared to the control group (p alpha 0.005). In the multivariate Cox regression model, older age (HR:1.05 IC95%1.01-1.09 p = 0.01), BMI > 40 (HR:13.2 IC95% 2.1-83.2 p = 0.01), and high activity of the underlying disease (HR:16 95% CI 3.7-69.4 p alpha 0.005) were associated with lower survival. Conclusion(s): In conclusion, patients diagnosed with AAV presented a worse disease course during SARS-CoV-2 infection with a more frequent requirement for invasive mechanical ventilation. Likewise, these patients showed lower survival compared to patients with other autoimmune diseases.
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Background: In 2018 we reported the emergence of the new HIV-1 recombinant CRF94-02BF2 involved in a large transmission cluster of 49 French MSM mostly infected in 2016-2017. This CRF94 raised concerns of enhanced virulence. Prevention actions were undertaken in the area and population affected. This study reported the molecular and epidemiological evolution of this CRF94 until June 2022. Method(s): In 2021-2022, French sequence databases were screened for patients infected with HIV-1 subtype CRF94 or similar strain. HIV subtyping was confirmed by phylogenetic analysis of genes encoding both protease and reverse transcriptase (1070bps), and integrase (696bps) using IQ-Tree. Five whole genomes, related but distinct from CRF94, were obtained with the DeepChek assay Whole Genome kits. Recombination breakpoints were estimated using RDP4 and SimPlot. Mann-Whitney and LogRank tests were used for statistical analyses to compare patients' characteristics. Result(s): In June 2022, 49 new HIV-1 sequences were collected: 14 clustered with the 49 previous CRF94, 32 formed a new cluster next to but distinct from CRF94, and 3 strains could not be classified. Analysis of 5 whole genomes from the new cluster revealed a new recombinant, the CRF132-94B, mainly consisting of CRF94 which recombined with subtype B in the POL and accessory genes. Vif gene changed from the F2 to the B subtype. Both CRF94 and 132 clusters involved >95% of MSM, mostly infected < 1 year before diagnosis. However, there were differences: 97% were diagnosed in 2013-2019 for CRF94 vs 90% in 2020-2022 for CRF132. At time of diagnosis, 33% of patients infected with CRF94 knew the Prep vs 95% for CRF132. In the cluster CRF94, patients were older (34 vs 30 years, p=0.02), had higher viral loads (5.42 vs 4.42 log10 copies/Ml;p< 0.001), a lower CD4 cell counts (358 vs 508 /mm3, p=0.002). On treatment, the patients with the CRF94 reached viremia < 50 copies/Ml significantly later than those infected with CRF132 (p=0.0002). The prevention activities targeting the CRF94 cluster could explained the few patients infected with this strain after 2018. The CRF132 is mainly located in another Paris region area, but no specific transmission place has been identified. Conclusion(s): After 2019, the CRF94 spread seems greatly slowed down but the very close CRF132-94B has given birth to a new highly active cluster in 2020- 2022, despite the COVID social-distancing and a strong knowledge of the Prep. CRF132 appears to be less virulent perhaps due to the Vif gene change. Identified breakpoints positions of the new HIV-1 CRF132-94B. GenBank accession numbers of the five references : ON901787 to ON901791.
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Introduction: The association of tracheostomy timing and clinical outcomes in ventilated COVID-19 patients remains controversial. Data from the pre-pandemic era has demonstrated the use of tracheostomy for ventilator weaning [1]. However, the use of tracheostomy in COVID- 19 patients was a subject of discussion [2]. Nevertheless, evidence of the impact of tracheostomy on the outcome in critically ill COVID patients is still lacking. This study aims to evaluate the impact on Intensive Care Unit (ICU) outcome (survival) of tracheostomy in COVID- 19 ventilated patients. Method(s): Monocentric descriptive observational study. Demographic and clinical data, timing of tracheostomy and outcome (ICU mortality) from 1st January to 31st December 2021 were registered. Analysis of descriptive statistics for continuous variables and survival analysis (log rank test). Result(s): 115 patients were included (72% males), all mechanically ventilated, 7 (6%) were subjected to tracheostomy. The mean age was 67.2 years (range 36-84 years). The ICU mortality was 62% (71). The group of patients not submitted to tracheostomy had a mean survival time of 24.4 days (SD +/- 1.5) and median survival time of 22 days (SD +/- 1.7). The group of patients that were subjected to tracheostomy, the mean survival time was 68.5 days (SD +/- 12.2) and median survival time was 50 days (SD +/- 2). This comparison is significative (Log Rank test, p = 0.0001). Conclusion(s): The present study demonstrates a better survival likelihood of the tracheostomized subpopulation. Tracheostomy was only done in 6% of patients, which elucidates a need to further prospective, randomized studies to assess the impact on the outcome of tracheostomy in ventilated COVID19 patients.
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Background: Previous studies have demonstrated promising serologic responses in PLWH receiving a third dose of vaccine against SARS-CoV-2. However, real-world clinical effectiveness, especially during the pandemic caused by B.1.1.529 variant, remains less investigated. Method(s): PLWH seeking HIV care at our hospital from 2021/6 to 2022/6 were included and advised to receive the third dose of COVID-19 vaccine. Individuals were excluded from this study if they had been previously diagnosed with COVID-19. Different types of COVID-19 vaccines were available in the vaccination program, including BNT162b2, mRNA-1273 (either 50 or 100 mug), MVC-COV1901 and NVX-CoV2373 vaccines. PLWH were screening for the occurrence of COVID-19 through the reporting system of notifiable diseases of Taiwan CDC, and were tested for anti-nucleocapsid (anti-N) IgG every 1 to 3 months. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, occurrence of SARS-CoV-2 infection, seroconversion of anti-N IgG, death, or loss to follow-up, whichever occurred first. Result(s): 1,496 PLWH were included: 631 (42.2%) receiving 100 mug mRNA-1273 vaccine, 468 (31.3%) 50 mug mRNA-1273 vaccine, and 328 (21.9%) BNT162b2 vaccine, 65 (4.3%) MVC-COV1901 vaccine, and 4 (0.3%) NVX-CoV2373 vaccine for the third dose of SARS-CoV-2 vaccination. 297 (19.9%) PLWH were diagnosed with COVID-19 during the follow-up period, including 92 (14.6%) who received 100 mug mRNA-1273, 111 (23.7%) 50 mug mRNA-1273, 79 (24.1%) BNT162b2 and 15 (21.7%) either MVC-COV1901 or NVX-CoV2373;in addition, 98 PLWH had seroconversion of anti-N IgG during follow-up, including 23, 50, 19 and 6 PLWH who received 100 mug mRNA-1273, 50 mug mRNA-1273, BNT162b2, and either MVC-COV1901 or NVX-CoV2373, respectively. Similar rates of new infection with SARS-CoV-2 or seroconversion of anti-N IgG were demonstrated regardless the vaccine type of the third dose (log-rank test, p=0.46). Factors associated with a diagnosis of SARS-CoV-2 infection and seroconversion of anti-N IgG included an age >50 years (aOR, 0.67;95% CI, 0.49-0.91) and newly infected with hepatitis C virus (HCV) (aOR, 1.41;95% CI, 1.09-1.83). Conclusion(s): Our study demonstrated that clinical effectiveness of the third dose of different vaccines available to PLWH was similar in preventing SARSCoV- 2 infection or seroconversion of anti-N IgG Taiwan. PLWH aged less than 50 years and those with newly diagnosed HCV infection were at higher risk of acquiring COVID-19. Kaplan-Meier survival curve for acquiring COVID-19 or seroconversion of anti-N IgG in PLWH receiving different COVID-19 vaccination of the third dose (log-rank test, 4 groups, p = 0.46).
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Background: Structural barriers to care among people who inject drugs (PWID) raise concerns about disproportionate access to essential services like COVID-19 vaccination. Given the heightened risk of serious complications resulting from SARS-CoV-2 infection, particularly among people living with HIV (PWH) with unsuppressed viral load, its critical to understand the role of HIV care among other factors associated with timely vaccination. We aimed to assess the role of HIV care on COVID-19 vaccination uptake among PWID. Method(s): We included 960 adult PWUD participating in the ALIVE (AIDS Linked to the Intravenous Experience) longitudinal study in Baltimore, Maryland, who were alive and in follow up as of April 2020. We ed COVID-19 vaccination data from electronic medical records linked to participants via the regional health information exchange. We conducted survival analysis to estimate time from broad vaccine eligibility (April 6, 2021) to completion of the COVID-19 vaccination primary series by HIV status (uninfected, virally suppressed PWH [HIV-RNA< 400 copies/mL], unsuppressed PWH [HIV-RNA >400 copies/mL]) and Cox Proportional Hazards regression to adjust for potential confounding by health status and substance use variables. Result(s): Our sample (N=960) was primarily black (77%) and male (65%) with 31% reporting recent injection drug use. Among 265 people living with HIV (PWH) in our sample (27%), 84% were virally suppressed. As of February 22, 2022, 539 (56%) completed the primary series, 131 (14%) received a single dose of mRNA vaccine and 290 (30%) remained unvaccinated. Compared to PWID without HIV, virally suppressed PWH were significantly more likely to complete the primary series (Adjusted Hazard Ratio [AHR]:1.23,95% Confidence Interval [95%CI]:1.07,1.50), while PWH with higher viral loads were less likely (AHR:0.72,95%CI:0.45,1.16). Sensitivity analyses with a subsample restricted to PWH confirmed significant differences in time to vaccination by viral load status (log-rank p-value: 0.016) and modeling with an origin of Dec. 12, 2020, yielded similar adjusted results. Conclusion(s): Among PWID with HIV, viral suppression is associated with quicker vaccination uptake, likely due to HIV care engagement. Alongside interventions targeting social determinants (e.g. low income, homelessness) and substance use behaviors (e.g. active injecting, stimulant use), targeted improvements along the HIV care continuum and other efforts to engage PWID may bolster vaccine uptake. Figure 1. Kaplan-Meier survival curve demonstrating time-to-vaccination (completion of COVID-19 primary series) in weeks by HIV status accounting for viral load (HIV-, HIV+ [VL <= 400 cells/muL], HIV+ [VL > 400 cells/muL]), including results for Log-rank tests for homogeneity among strata (p-value).
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INTRODUCTION: Patients with COVID-19 can develop myocarditis due to respiratory hypoxemia, hyperinflammation, as well as direct injury due to binding of the virus to the angiotensin-converting enzyme 2 receptors in myocyte. In this study we examined the association between myocarditis among COVID-19 hospitalizations and adverse hospital outcomes. HYPOTHESIS: We hypothesized that adverse hospital outcomes such as in-hospital mortality, cardiac arrest, cardiogenic shock, mechanical ventilation, and acute respiratory distress syndrome would be higher among COVID-19 hospitalizations with myocarditis. METHOD(S): The current study was a retrospective analysis of data collected in California State Inpatient Database (SID) during 2020. All hospitalizations for COVID-19 were included for the analysis. ICD-10-CM diagnosis was used to identify COVID-19 (U07.1) and myocarditis hospitalizations and other procedures and conditions. Propensity score match analysis, survival analysis, and conditional logistic regression were done to compare adverse clinical outcomes between COVID-19 patients with and without myocarditis. RESULT(S): A total of 164,368 COVID-19 hospitalizations were included for the analysis. Among them, 575 (0.4%) hospitalizations had myocarditis. Prior to propensity score matching, the rate of in-hospital mortality was significantly higher among COVID-19 hospitalizations with myocarditis (29.8% versus 14.0%, P<0.001). Even after propensity score matching, the rate of in-hospital mortality was significantly higher among the myocarditis group (30.0% versus 17.5%, P<0.001). Supporting this finding, survival analysis with log-rank test also showed that 30-day survival rates were significantly lower among those with myocarditis (39.5% versus 46.3%, P<0.001). Conditional logistic regression analysis showed that the odds of cardiac arrest (OR,1.90;95% CI, 1.16-3.14), cardiogenic shock (OR,4.13;95% CI, 2.14-7.99), mechanical ventilation (OR,3.30 (2.47-4.41), and acute respiratory distress syndrome (OR, 2.49;95% CI, 1.70-3.66) were significantly higher among those with myocarditis. CONCLUSION(S): Our study using a large administrative database found that myocarditis was associated with greater rates of in-hospital mortality and adverse hospital outcomes among COVID-19 patients. Early suspicion is important for prompt diagnosis and timely management.Copyright © 2022
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Introduction: Tocilizumab is associated with positive outcomes and decreased mortality in severe covid-19. Objective(s): To elaborate on clinical features associated with worse outcomes in tocilizumab treated patients. Method(s): Retrospective multi-center, investigating mortality, intubation and non-invasive ventilation (NIV) 90 days from diagnosis in tocilizumab treated severe progressive covid-19. Result(s): 121 subjects, 62% males. 96 (79.4%) survived, 25 died (20.6%). Compared to survivors, non-survivors (NS) were older (median 57 vs 75 years), had more comorbidities, higher rates of intubation (p<0,05). On admission, NS had lower PO2/FiO2 ratio, higher blood ferritin and higher troponin (281 vs 214, 587 vs 1,271, 9.4 vs 24) and on clinical progression (day of tocilizumab treatment) had lower PO2/FiO2 ratio, decreased lymphocytes, increased neutrophil to lymphocyte ratio, increased ferritin and lactate dehydrogenase (LDH), disease located centrally on computed tomography scan and increased late c-reactive protein (150 vs 100, 860 vs 560, 6.8 vs 16.6, 674 vs 1,565, 354 vs 530, 5% vs 21%, 0.09 vs 7.6, respectively). Cox proportional hazards regression analysis identified age and LDH as predictors of death, admission PO2/FiO2 and progression LDH as predictors of intubation, PO2/FiO2 ratios, progression LDH and central lung disease as predictors of NIV (a<0,05). Log-rank test of mortality yielded the same results. ROC analysis of above predictors in a separate validation cohort yielded significant results. Conclusion(s): Older age and serum LDH predict mortality in tocilizumab treated severe covid-19. Hypoxia levels, LDH and central pulmonary involvement are associated with intubation and NIV.
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Background: The transmission and the fatality rates of coronavirus disease 2019 (COVID-19) are high enough to cause the strain of intensive care resources, and even influence the treatment and prognosis of non-COVID-19 patients. Therefore, the collateral damages to non-COVID-19 critically ill patients before and during the COVID-19 pandemic were evaluated. Method(s): Demographic data, severity, clinical course, and prognosis of non-COVID-19 patients admitted to the intensive care unit (ICU) via the emergency room (ER) before and during the COVID-19 pandemic were acquired from electronic medical records from three university-affiliated tertiary hospitals. Result(s): A total of 619 patients before and 542 patients during the pandemic were enrolled. During the COVID-19 pandemic, simplified acute physiology score (SAPS) 3 and the sequential organ failure assessment score (SOFA) on ER admission (SAPS3 72.7 +/- 20.3 versus 65.9 +/- 18.6, p <0.001, respectively;SOFA score 8.1 +/- 4.2, versus 7.2 +/-4.2, p <0.001, respectively) were significantly higher than those before the pandemic. The length of stay in the ER, ICU, and hospital was longer (p<0.05 in all). Finally, the hospital mortality rate was significantly higher during the pandemic than those before (39.7% versus 28.4%, p<0.001). The overall survival in the Kaplan-Meier curve analysis with log-rank test was significantly higher during the pandemic (p=0.04). Conclusion(s): These result of increased severity, hospital day and mortality in non-COVID-19 patients indicate the collateral damage to non-COVID-19 patients due to shortages in medical resources for them. Strategic management of medical resources is required to halt these consequences.
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Introduction: Coronavirus disease 2019 (COVID-19) causes abnormalities in the hemostatic system, which are referred to as COVID-associated coagulopathy. Whole blood viscoelastic studies, such as thromboelastography (TEG), are the best way to determine the dynamics of clot formation. The hypercoagulable state seen in COVID-19 patients is aggravated by a severe state of fibrinolysis shutdown, which is caused by overexpression of plasminogen activator inhibitor 1 and thrombin activated fibrinolysis inhibitor. Method(s): An automated thromboelastogram was used to perform TEG on 28 COVID-19 patients. Based on TEG parameters such as R-time, K-time, alpha angle, maximum amplitude (MA), and clotting index (CI), the hemostatic state was classified as hypercoagulable in 17 (63 percent), hypocoagulable in 2 (7 percent), or normal in 8 (30 percent) patients. Result(s): Twenty-seven patients were included, with a median age of 50 years (IQR 40-60 years) and a male to female ratio of 0.9:1. COVID-19 was mild in 6 (22.2%), moderate in 2 (7.4%), and severe in 19 (70.4%) patients. Fibrinolytic shutdown was detected in 4 (15%) patients. TEG analysis revealed that they were hypercoagulable. All four patients showed high D-dimer levels and a LY-30 of 0%, as well as decreased K-time and increased alpha angle or MA. Conclusion(s): Despite thromboprophylaxis, hypercoagulable states and severe inflammatory states are prevalent in COVID-19 patients. Patients with hypocoagulable and hypercoagulable conditions had greater 28-day mortality than those with normal coagulation. (Log-rank test, P=0.002). Only two of the four patients who had their fibrinolytic systems turned down survived. These patients had no clinically evident thrombosis.
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Introduction: With more people working from home after the COVID pandemic, it is of utmost importance to further understand the impact of social isolation on outcomes of patients with coronary atherosclerosis. Our preliminary studies have shown that the novel diet-inducible, fatal mouse model of coronary atherosclerosis, SR-BIDELTACT/LDLR KO, tend to die on average around 4-6 weeks after starting a high-fat Paigan diet (HFD). This mouse model can be used to further understand the effect of social isolation on cardiovascular disease. We hypothesize that social isolation will decrease survival and worsen cardiac function. Method(s): Male and female SR-BIDELTACT/LDLR KO mice were put into social isolation (n=11), in a group of 2-3 (n=13), or in a group of 4-5 (n=22). At six-weeks-old, mice were started on a HFD to induce pathology. Echocardiography was performed to assess cardiac function. Analysis was performed using one-way Analysis of Variance tests and hoc-Tukey's Honest Significant Difference tests. A log-rank test was used to calculate the difference in survival distributions. Result(s): Mice living in groups of 1, 2-3, and 4-5 lived for an average of 34.9, 35.6, and 41.5 days, respectively, after starting the HFD (Fig. 1A). The survival distribution is significantly different between the mice in isolation versus the mice in groups of 4-5 (p<;0.01). Mice in social isolation have significantly lower ejection fractions than mice living in groups of 4-5 after two weeks of being on the HFD (Fig. 1B, p=0.028). Conclusion(s): Mice in social isolation exhibited decreased survival and reduced ejection fractions compared to mice in groups of 4-5. More mice would be needed to determine whether single isolation is different from mice in groups of 2-3. Further studies should be performed to understand the mechanism underlying the effect of social isolation on heart function. Such studies may influence future prevention strategies to positively affect outcomes of patients with atherosclerosis. (Figure Presented).
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Background. Nirmatrelvir with ritonavir (nirmatrelvir/r) is an oral antiviral COVID-19 treatment. We report its efficacy to shorten time to sustained alleviation and resolution of COVID-19 signs/symptoms in nonhospitalized adults with COVID-19 at high risk of severe disease as of primary completion data cut (11 Dec 2021). Methods. In this phase 2/3 double-blind study, eligible adults with confirmed SARS-CoV-2 and <= 5 days (d) of symptoms were randomized 1:1 to nirmatrelvir/r 300 mg/100 mg or placebo (PBO) every 12 hrs for 5 d. Pts logged presence and severity (on 3- or 4-point scales) of prespecified COVID-19 signs/symptoms daily Day 1 (predose) through 28. Times to sustained alleviation and resolution of all targeted signs/ symptoms were assessed, summarized with Kaplan-Meier curves, and compared by treatment by log-rank test. Individual signs/symptoms were compared with descriptive analyses. Results. From Jul-Dec 2021, 2246 pts enrolled;2085 pts (nirmatrelvir/r, n=1039;PBO, n=1046) met criteria for the mITT1 population (<= 5 d of symptom onset, did not/not expected to receive an mAb). More pts achieved sustained alleviation or sustained resolution with nirmatrelvir/r. Shorter median times to sustained alleviation/ resolution were observed with nirmatrelvir/r (13/16 d) vs PBO (15/19 d;Fig 1 & 2). Also, a shorter median time to sustained alleviation was seen in pts treated <= 3 d of symptoms with nirmatrelvir/r (12 d) vs PBO (15 d). The most common symptoms were cough, muscle/body aches, and headache in both groups. The median time to sustained alleviation of cough and headache was 2 d less with nirmatrelvir/r vs PBO. The median time to sustained resolution of muscle aches and shortness of breath was 3 d and 4 d less with nirmatrelvir/r. The proportion of pts with severe signs/symptoms in the nirmatrelvir/r vs PBO group was significantly higher at baseline, but significantly lower after treatment, showing nirmatrelvir/r significantly reduced symptom severity through Day 28 (Fig 3). Pts who were seronegative vs seropositive or had high vs low viral load at baseline achieved faster times to sustained alleviation with nirmatrelvir/r vs PBO. Conclusion. Nirmatrelvir/r treatment reduced duration and severity of COVID-19 symptoms vs PBO in pts at high risk of progressing to severe disease. NCT04960202.
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Background. Remdesivir (RDV) has been a mainstay of COVID-19 therapy for hospitalized patients. Impact of RDV timing in relationship to symptom-onset in hospitalized patients remains unclear, though early treatment is theorized to improve antiviral activity and clinical outcomes. Methods. This was a single-center retrospective study of adult patients hospitalized for severe COVID-19 treated with RDV. Patient charts were reviewed by 2 independent investigators to determine disease course and outcomes. Patients were stratified based on time from symptom-onset to RDV (short: <=7 vs. long: >7 days). The primary outcome was time to clinical recovery within 28 days. Secondary outcomes were proportion of patients recovered and proportion discharged from the hospital within 10, 14, and 28 days;and mortality within 28 days. Time to recovery was analyzed using the Kaplan-Meier method and the significance was tested by log rank tests. Cox's proportional hazards models were used to estimate hazard ratios (HR). Fisher's exact test was used to compare recovery rates between groups. Results. Overall, 405 patient charts were reviewed, and 337 met the inclusion criteria. On the first day of RDV, 178 (53%) of patients had symptoms for <7 days, while 159 (47%) of patients had symptoms for >7 days. Patients in the short symptom duration group were slightly older (66.5 vs. 59 years, p=0.004) and had more comorbidities. Median time to recovery was 7 (95% CI 5-9) in the short- vs. 5 (95% CI 4-6) days in the long-symptom duration groups, respectively, p=0.066. By day 10, 111 (62%) vs. 116 (73%) patients met the clinical recovery definition (p=0.048), and 113 (63%) vs. 119 (75%) patients were discharged from the hospital (p=0.026) in the short- vs. long-symptom duration groups, respectively. In the Cox's proportional hazards model, age, disease severity, and co-morbidities (kidney, liver, chronic respiratory diseases, and type II diabetes mellitus) were associated with longer recovery times. Conclusion. In this cohort, long duration of symptoms ( >7 days) prior to initiation of RDV therapy was not associated with longer recovery time or longer hospitalization. Additional studies are needed to elucidate benefits of RDV therapy in relationship to the time course of severe COVID-19 in hospitalized patients.
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Introduction: Coronavirus disease 2019 (COVID-19) causes abnormalities in the hemostatic system, which are referred to as COVIDassociated coagulopathy. Whole blood viscoelastic studies, such as thromboelastography (TEG), are the best way to determine the dynamics of clot formation. The hypercoagulable state seen in COVID-19 patients is aggravated by a severe state of ''fibrinolysis shutdown,'' which is caused by overexpression of plasminogen activator inhibitor 1 and thrombin activated fibrinolysis inhibitor. Aims & Objectives: We aimed to study the coagulation pattern in COVID-19 patients on TEG and explored the predictors of outcomes in our patients. Material(s) and Method(s): An automated thromboelastogram was used to perform TEG on 28 COVID-19 patients. Based on TEG parameters such as R-time, K-time, alpha angle, maximum amplitude (MA), and clotting index (CI), the hemostatic state was classified as hypercoagulable in 17 (63 percent), hypocoagulable in 2 (7 percent), or normal in 8 (30 percent) patients. Result(s): Twenty-seven patients were included, with a median age of 50 years (IQR 40-60 years) and a male to female ratio of 0.9:1. COVID-19 was mild in 6 (22.2%), moderate in 2 (7.4%), and severe in 19 (70.4%) patients. Fibrinolytic shutdown was detected in 4 (15%) patients. TEG analysis revealed that they were hypercoagulable. All four patients showed high D-dimer levels and a LY-30 of 0%, as well as decreased K-time and increased alpha angle or MA. Conclusion(s): Despite thromboprophylaxis, hypercoagulable states and severe inflammatory states are prevalent in COVID-19 patients. Patients with hypocoagulable and hypercoagulable conditions had greater 28-day mortality than those with normal coagulation. (Logrank test, P = 0.002). Only two of the four patients who had their fibrinolytic systems turned down survived. These patients had no clinically evident thrombosis.
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Purpose: This study assessed outcomes of hepatitis C virus (HCV) donor positive to recipient negative (D+/R-) kidney transplants (KT) in high immunologic risk patients. Literature reports positive short-term outcomes in low immunologic risk patients, but limited data exists to support HCV D+/R- KT in high immunologic risk patients. Method(s): This retrospective cohort study included HCV antibody negative (-) recipients of a nucleic acid test (NAT) positive (+) KT who received HCV treatment with direct-acting antiviral therapy from 12/1/20 and 11/30/21. NAT+ KT recipients were matched 1:1 with NAT - KT recipients based on age, body mass index, and gender. All serologies were confirmed prior to study inclusion. The primary outcome was a composite of patient and graft survival 3 months post-KT. Secondary outcomes included percent of patients with sustained virologic response (SVR), time to HCV treatment initiation, incidence of cytomegalovirus (CMV) and BK viremia, presence of de novo donor specific antibody (DSA), rejection and HCV treatment related adverse drug reactions (ADRs). Descriptive statistics were used for baseline characteristics and a Log-Rank test was used for the primary outcome. Result(s): Eighteen HCV NAT+ KT recipients were matched with 18 HCV NAT- KT recipients. Study population was similar between groups and had end stage renal disease due to diabetes and/or hypertension, mean class I PRA >14%, pre-transplant DSA in 16% of patients in each cohort, and all received induction with rabbit anti-thymocyte globulin (Table 1). There was no difference in patient (p=0.32) and graft survival (p=0.99) between groups at 3 months post-KT. One death due to COVID-19 occurred in the NAT- group. There was no difference in estimated glomerular filtration rate (eGFR) at 1 (p=0.39) and 3 months (p=0.28), incidence of delayed graft function (DGF) (p= 0.67) or CMV (p=0.1) and BK viremia (p=1) between groups. (Table 2). HCV transmission occurred in all NAT+ KT recipients, and all who completed therapy achieved SVR. Treatment was initiated on average 8.5 weeks post-KT (Table 3). Notably, 33% of patients required financial assistance to obtain HCV treatment. Conclusion(s): Use of HCV D+/R- KT resulted in no difference in patient and graft survival at 3 months in this matched cohort. HCV NAT + KT patients should be connected with financial assistance programs early to promote timely treatment initiation. (Table Presented).
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Background: ICI revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Here we investigated the anti-tumoral effect of Allocetra—OTS cellular therapy, in solid tumor models. Methods: Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis.Balb/c mice were inoculated in the peritoneal cavity with AB12 (mesothelioma) stably transduced with pLenti-PGK-V5-Luc-Neo for IVIS visualization and treated with anti-CTLA4, anti-PD1, or cisplatin, with or without Allocetra-OTS (also administered as monotherapy). Kaplan-Meier log rank test was done for survival. CAR T model was induced in SCID-Bg mice were inoculated intraperitoneally with human HeLa-CD19, followed by treatment with 10×109 cells of Allocetra-OTS or vehicle, and 1×107 CD19-CAR T cells or mock T cells. Results: Anti-CTLA4 therapy significantly improved survival from mean 34±9 to 44.9 ±20 days (p<0.05). However, Allocetra-OTS monotherapy improved survival to 52.3 ±20 days (p<0.02) and anti-CTLA4 + Allocetra-OTS combination therapy to 86.7±20 days (p<0.0001) with complete cancer remission in 60-100% of mice. Similar results were seen in combination therapy with either anti-PD1 or cisplatin. In the CAR-T model, SCID-Bg mice survived 30±5 days (range 27–37) and were sacrificed or died from tumor progression. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly improved survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further improved survival to 75±10 (p < 0.001) with 20-40% complete remission. Conclusions: During intraperitoneal tumor progression, Allocetra-OTS as monotherapy or in combination with ICI, cisplatin or CAR-T therapy, significantly reduced tumor size and resulted in complete remission in up to100% treated mice. Based on excellent safety profile in > 40 patients treated in prior clinical trials for sepsis and COVID-19, phase I/II clinical trial of Allocetra-OTS plus chemotherapy is planned for Q3 2022, and a second phase I/II clinical trial of Allocetra-OTS plus anti-PD1, as a second- and third-line therapy in various cancers, is planned for Q4 2022. Legal entity responsible for the study: The authors. Funding: Enlivex Therapeutics Ltd. Disclosure: D. Mevorach: Financial Interests, Personal, Royalties, Founder & CSO: Enlivex Therapeutics LTD. E. Yalon, E. Regev, C. Ankri, O. Hershkovitz, Y. Shabat, B. Reicher: Financial Interests, Personal, Full or part-time Employment: Enlivex Therapeutics LTD.
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Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.
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Background: Severe SARS-CoV-2 infections associated with high mortality rates are reported in a higher percentage of patients (pts) with hematologic malignancies compared to general population. In chronic myeloid leukemia (CML), pts with uncontrolled disease have a higher mortality risk. The impact of SARS-CoV-2 infection on CML pts in treatment-free remission (TFR) has not been studied so far. In particular, as immune control of residual disease may be important for TFR, the concern is that the infection could induce loss of TFR. Aims: To evaluate the outcome of SARS-CoV-2 infection in CML pts in TFR and assess any impact on maintenance of TFR. Methods: From March 2020 to December 2021, the CANDID study organized by the international CML Foundation has collected data on COVID-19 positive CML pts worldwide. Details on the registry were presented recently (Pagano ASH 2021). For this sub-analysis on pts in TFR additional information were collected including;molecular remission status (BCR::ABL1 ratios) before, during and after SARS-CoV-2 infection covering at least 6 months. For molecular analyses, BCR::ABL1 ratios were classified according to Cross et al (Leukemia 2015). In addition, ratios of 0% without indication of sensitivity were allocated as MR4 i.e. 0.01%IS. PCR outlier results were identified using the ROUT method by nonlinear regression with a maximum false discovery rate (FDR) of 1% (Motulsky et al 2006). Time to molecular relapse (MR) was measured from the date of COVID-19 diagnosis to the date of MR defined as loss of major molecular remission (MMR, BCR::ABL1 >0.1%IS) or the date of last molecular test. Molecular relapse-free survival (MRFS) and overall survival (OS) were estimated with the Kaplan-Meier method. The statistical difference between groups was performed using log-rank test. Results: By December 2021, 1050 COVID-19 positive CML pts were registered. 95 pts were in TFR at the time point of SARS-CoV-2 infection of which 89 (93.68%) recovered and 6 deceased (6.32%). Median age of TFR pts was 57 years, male were 51 (53.68%). Median time from CML diagnosis to reporting date was 13 years (range 3.7-27.0 years). TFR duration was 2.83 years in median (range 0.5 months - 10.1 years) including 19 pts with a duration < 1 year. From the 89 recovered TFR pts, 74 pts completed the 6-month follow up (83%), a further 6 pts with molecular follow-up of 3-5 months after COVID-19 diagnosis were still in TFR, 9 pts were lost to follow-up. Of 74 pts with complete reports, 69 pts remained in TFR (93%) and 5 pts lost TFR. For 71 pts, PCR results were obtained before, during and after infection. With the ROUT method 10 pts demonstrated outlier PCR tests, 61 pts demonstrated stable PCR results. There was no statistically significant difference in PCR results before and during/after infection (p>0.2). MRFS for these 71 pts 15 months after COVID-19 diagnosis was 86%. Probability of TFR loss was higher in pts with a TFR duration < 6 months compared to pts with TFR duration >6 months (27% vs 10%, Fig 1A). Additionally, there were no statistically differences in hospitalization rate (16% vs 23%, p=0.12) and severity of COVID-19 symptoms (12.6% vs 12%, p=0.87) comparing TFR and TKI treated pts. OS of COVID-19 positive TFR pts did not differ from COVID-19 positive pts on TKI therapy (HR 1.1, CI 0.47-2.54) (Fig 1B). Summary/Conclusion: In this sub-analysis of the CANDID study, CML pts in TFR had similar severity and survival to CML pts who were on TKI therapy and there was no evidence of an increased risk of TFR loss after SARS-CoV-2 infection.
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Background: Optimal consolidation for young R/R FL in the rituximab age remains uncertain and the benefit of ASCT is not clearly established. Aims: The FIL FLAZ12 trial (NCT01827605) is a prospective, multicenter, randomized, phase 3 trial, comparing RIT versus ASCT, as consolidation after chemoimmunotherapy, both followed by R maintenance in R/R FL. Methods: Pts aged 18-65 yrs, with R/R FL after 1 or 2 lines of chemoimmunotherapy, without significant comorbidities were enrolled. Patients received 3 courses of therapy chosen by the investigator among RCHOP, R-DHAP, R-FM, R-ICE, R-IEV or R-B. Pts achieving at least PR (according to Cheson et al. 2007) were randomized 1:1 to either RIT or ASCT before CD34+ collection. Conditioning for ASCT was BEAM or TEAM. RIT was given as previously described (Morschhauser et al., 2008). After consolidation, pts received R maintenance every 3 months for eight courses. Primary endpoint was PFS. Considering ASCT toxicity, it was hypothesized to be a superior choice, if capable of increasing 3-years PFS from 40% to 60% (two-side log-rank test with alpha of 5% and a power of 85%). Clinical secondary endpoints were ORR, CRR, OS, EFS and TTF. Results: Between Aug 2012, and Sep 2019, 164 pts were screened and 159 enrolled by 38 FIL Centers (enrolled population). Unfortunately, the study was prematurely closed due to low accrual. The data were analyzed on an ITT basis on May 2, 2021 with a median follow-up (mFU) from enrollment of 43 months and 75 PFS events. The two arms were clinically well balanced, with median age of 57 yrs (IQR 49-62), 55% male, 57% stage IV, 20% bulky disease. Tumor re-biopsy was performed in 79% pts. POD-24, retrospectively assessed was observed in 32% of pts. Two pts (1%) did not start treatment (non-confirmed histology and withdrawal). Sixteen (10%) pts discontinued before randomization (7 SD, 3 PD, 3 AE, 1 withdrawal, 2 poor compliance) and 141 (89%) were randomized to either RIT (71) or ASCT (70) (randomized population). Of these 19 (13%) (RIT 8, ASCT 11) did not receive the planned consolidation due to 7 PD, 4 AE, 1 medical decision, 2 poor mobilization, 2 withdrawals, 1 poor compliance, 2 protocol breaches, while 63 (89%) received RIT and 59 (84%) ASCT. After RIT, 61% of pts achieved CR and 23% PR, while after ASCT these were 70% and 9%. Estimated PFS at 3 yrs was 60% (95% CI: 46%-71%) in the RIT arm vs. 59% (95% CI:45%-70%) in the ASCT arm, p = 0.8613 (HR 0.96, 95%CI: 0.57,1.59). (Figure 1) 3yrs-OS was again superimposable in the two arms: 83% (95%CI: 69%-91%) in the RIT vs 85% (95% CI: 72%-91%) in the ASCT, p = 0.8310 (HR 1.10, 95%CI: 0.45,2.72). Grade ≥ 3 hematological toxicity was 46% in the RIT vs 94% in the ASCT arm (p < 0.001). For ASCT vs RIT grade ≥3 neutropenia occurred in 94% vs 41% of pts (p < 0.001). During follow-up, 4 pts died in remission: 1 AML (RIT), 2 SARS-COV2 infections (RIT) and 1 pneumonia (ASCT). Second cancers occurred in 3 pts after RIT and 7 after ASCT (p = 0.480). Multivariable analysis for PFS indicated POD-24, male sex, LDH and refractory disease as adverse parameters. Subgroup analysis for PFS including gender, age, LDH, POD-24 and extranodal disease show no subgroup favoring RIT nor ASCT. Image: Summary/Conclusion: Even if prematurely interrupted, our study demonstrated no meaningful difference in efficacy between ASCT and RIT, but ASCT was more toxic and more demanding for pts and health service. Both strategies induced a similar and favorable long-term outcome suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.