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Purpose: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if pre-vaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Method(s): A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, with comparison to 16 healthy controls (HCs). Anti-spike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detectionbased multiplexed sandwich immunoassays were used to quantify plasma cytokine and chemokine concentrations (n=20 analytes). Concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine, were compared using Wilcoxon-rank-sum test with false discovery rates (FDR) computed to correct for multiple comparisons. Result(s): In the study population, 100% of HCs, 59% of SOTRs after two doses and 63% of SOTRs after three doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in cytokine levels between SOTRs with high vs low-titer antibodies after two doses of vaccine. However, as compared to poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher pre-third dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1alpha, and TNF-alpha (FDR <0.05). Conclusion(s): A specific inflammatory profile or immune state may identify which SOTRs are likely to develop stronger sero-response and possible protection after a third dose of SARS-CoV-2 vaccine.
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Background: Etavopivat, an investigational, once-daily, selective, activator of erythrocyte pyruvate kinase (PKR) increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers and patients (pts) with sickle cell disease (SCD).1,2 Aims: We report results of an open-label (OL) extension cohort from a Phase 1 study (NCT03815695) designed to characterize the safety and clinical activity of etavopivat at a maximal pharmacodynamic dose in pts with SCD. Methods: 15 pts were enrolled to receive etavopivat 400 mg once daily for 12 wks, followed by a 4-wk follow-up. Assessments included safety, pharmacokinetics, pharmacodynamics, RBC health parameters and systemic markers of SCD pathophysiology. Results: Of 15 pts (age 32.3 ±10.1 yr;HbSS/SC n=13/2), 14 completed 12-wks of treatment (tx);1 pt discontinued tx after ∼2 wks. Etavopivat 400 mg once daily was generally well tolerated. Adverse events (AEs) reported during tx and follow-up were commonly low grade (Gr) and consistent with pts' SCD. Gr1-2 AEs in >2 pts (n [%]) were sickle cell pain events (9 [60%]);headache (5 [33%]);and upper respiratory tract infection (3 [20%]). The Gr3-4 AE in >1 pt was sickle cell vaso-occlusion (VOC;4 [27%]). On-tx serious adverse events (SAEs;1 pt each) were Gr3 VOC post Gr3 COVID (not tx-related) and Gr3 left femoral deep vein thrombosis (possibly related, resulting in tx discontinuation as stated above). SAEs (1 pt each) during the 4-wk follow-up were Gr3 acute chest syndrome + Gr3 VOC, Gr3 non-cardiac chest pain and Gr3 syncope (all unrelated). Observed increases in ATP and decreases in 2,3-DPG were durable over 12 wks of etavopivat tx. Etavopivat tx normalized hemoglobin (Hb)S-oxygen affinity to that of HbA. Etavopivat tx over 12 wks improved overall sickle RBC health, demonstrated by a reduction in point of sickling as well as improved measures of deformability and hydration of sickle RBCs (all P<0.01;Figure). Etavopivat tx over 12 wks was associated with a sustained significant increase in Hb compared with baseline (BL;P<0.0001), with mean maximal increase of 1.5 (range 0.7-2.3) g/dL. Ontx increase in Hb >1g/dL was achieved in 11 (73%) pts, for whom the mean maximal Hb increase was 1.8 (1.2-2.3) g/dL. Absolute reticulocytes, indirect bilirubin and lactate dehydrogenase significantly decreased from BL and were sustained over the 12wk period (all P<0.05), indicative of increased RBC lifespan and decreased hemolysis. Several markers of disease activity significantly decreased from BL during daily etavopivat tx, including the inflammatory marker tumor necrosis factor-α , which decreased by 35% (P<0.001). Based on preliminary exploratory analysis with an aggregate duration of etavopivat exposure of 3.32 pt-yrs in the OL cohort, a decrease in the trend for VOC Hospitalizations was observed: annualized historical and on-tx VOC Hospitalization rates were 0.93 and 0.30, respectively;the 1 on-tx VOC Hospitalization was COVID-related. Summary/Conclusion: Etavopivat 400 mg once daily for up to 12 wks demonstrated a tolerable safety profile and showed improvements in various markers of RBC health in pts with SCD. Rapid and sustained increases in Hb were associated with decreases in reticulocyte counts and markers of hemolysis, supporting increased sickle RBC lifespan and improved anemia. Together, these results support further evaluation of etavopivat in the Phase 2/3 Hibiscus Study (NCT04624659) currently enrolling pts. (Figure Presented).
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Background: Historically, control of HIV infection in young men living with HIV (LWH) has been problematic. We examined the STI/HIV burden in young men with urethral discharge syndrome (UDS) in Kampala, Uganda. Methods: Between Oct 2019-Nov 2020, 250 men with UDS were enrolled at 6 urban sites. All HIV positive men (20%, 50/250) had plasma viral load testing (Abbott m2000 RealTime HIV-1);when VL>1000 copies/mL, resistance and recency testing (Asanté HIV-1 Rapid Recency Assay, Sedia Biosciences) were performed. Penile meatal swabs were retrospectively tested for gonorrhea, chlamydia, trichomoniasis, and Mycoplasma genitalium (Hologic Aptima CT/NG, TV, MG). Descriptive statistical analysis, logistic, and bivariable and multivariable regression were undertaken. Results: Among the men LWH, 92% (46/50) had VL<1000;4 were not suppressed, 1 of whom was previously undiagnosed. Among the viremic individuals, no major resistance mutations were found and none appeared recently infected. Men (median age 24[22;32]) reported sex partners/previous 2 months (median 2[1;2]), 61.6% engaged in transactional sex in the previous 6 months, and 48.4% reported alcohol use. 44.4% reported alcohol use before sex in the previous 6 months. Overall, 0.4% reported 'always' condom use, 21.8% continued condomless sex since onset of UDS symptoms. There was a high burden of active, undiagnosed STIs found in these men (see Table);of the 10% who had syphilis, 80% were previously undiagnosed. Agreement between HIV-and syphilis-POC and lab-based testing was 100% and 95% (19/20), respectively. By multivariable logistic regression, alcohol use (OR, 3.32 (95% CI:1.61, 7.11)), and condomless sexual activity since symptom onset (OR, 2.86 (95% CI:1.20, 6.84)) were significantly associated with HIV;92% had at least one other STI. Conclusion: Among men presenting with UDS, bacterial STIs were very common. 20% had HIV with a surprisingly high level of viral suppression and no evidence of resistance in those with detectable VL. Recency testing results were non-discriminatory;none appeared recently infected. Risk of future HIV acquisition is high in those not LWH. Given the high frequency of bacterial STI, alcohol use and unprotected high-risk sexual behavior in this population, men with UDS who test negative for HIV should be prioritized for PrEP. Future research, evaluating the effect of SARS-CoV-2 on the burden of STI and level of viral suppression in this population, is required.
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Background: Seroprevalence studies of antibodies to SARS-CoV-2 are important for public health surveillance. Recent studies have shown that antibodies to SARS-CoV-2, both from natural infection and vaccination, decrease with time from exposure. Variation in the performance of antibody assays will impact the estimates of SARS-CoV-2 exposure and vaccination levels in a population. Using standardized serial dilutions, we evaluated 17 SARS-CoV-2 assays to establish an approximate limit of detection for each assay. Methods: The evaluated assays consisted of three chemiluminescent immunoassays (CLIAs), eight standard enzyme-linked immunosorbent assays (ELISAs), and six lateral flow assays (LFAs). All assays either evaluated IgG antibodies or total antibodies to SARS-CoV-2. The target antigen of 14 assays was the spike protein (S) or receptor binding domain (RBD);three assays evaluated antibodies to the nucleocapsid protein (N). A human SARS-CoV-2 serology standard with a WHO SARS-CoV-2 Serology International Standard binding antibody units (BAU) value of 764 BAU/mL to spike IgG and 681 BAU/mL to nucleocapsid IgG was obtained from the Frederick National Laboratory for Cancer Research. Half-logarithmic serial dilutions of the standard were then run in triplicate on each assay. Results: The MSD V-Plex chemiluminescent immunoassays (CLIAs) were the most sensitive by three logs, with positive results at a dilution greater than 1:106 (Figure). Standard ELISAs were less sensitive, with limits of detection ranging from dilutions of 1:20 (Euroimmun NeutraLISA) to 1:1620 (Euroimmun SARS-CoV-2 IgG and Euroimmun QuantiVac). Lateral flow assays (LFAs) were the least sensitive, with only one assay (Wondfo Colloidal Gold) having at least one positive result with a dilution greater than 1:180. Conclusion: As population seroprevalence to SARS-CoV-2 continues to rise, tests with a high limit of detection will be crucial for surveillance studies. As antibody levels decline after vaccination or infection, our data indicate that CLIAs like the MSD assay may provide the best opportunity to capture asymptomatic cases and individuals with low antibody titers.
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Aim: To investigate the prevalence and variations in precipitating causes of diabetes-related ketoacidosis (DKA) across hospitals and types of diabetes across the West Midlands. Methods: All people admitted with DKA from 1 January 2021 and 30 September 2021 in six hospitals in West Midlands as part of DEKODE database were included in this study. Precipitating causes were categorised as: excess alcohol-associated, covid-19 related, drug-induced, inter-current illness, new diagnosis of diabetes, sepsis, SGLT2 inhibitor related, suboptimal compliance to treatment, surgical, and unknown. Results from each of the participating hospitals are reported as frequencies and proportion anonymously. The differences in frequencies of precipitating causes by hospitals and type of diabetes were analysed by Kruskal-Wallis and Mann-Whitney U test respectively. Results: A total of 377 episodes were identified. Overall, inter-current illness (37.4%, n = 141) and suboptimal compliance to treatment (26.8%, n = 101) were the main precipitating causes of DKA. covid-19 contributed to 7.4% of episodes. While there were no significant differences between precipitating causes of DKA in people with type 1 (n = 210) and type 2 (n = 113) diabetes (p = 0.173), we noticed a variation across hospitals (p = 0.035). For example, hospital A had a higher prevalence of inter-current illness (44.4% vs 23.3%) and lower frequency of suboptimal compliance to treatment (18.8% vs 34.3%) compared to hospital B. Conclusion: Intercurrent illness and sub-optimal compliance remain common causes of DKA regardless of diabetes type. The DEKODE database allows rapid analysis of regional DKA data for both research and clinical care.
ABSTRACT
COVID-19 has affected people all over the world. For those who were infected by the virus, the repercussions go beyond immediate medical conditions to include social stigma, fear, uncertainty, and lifestyle changes. This study presents data collected as part of a mental health intervention (COVID Response) with individuals who had been diagnosed with coronavirus and had completed the minimum 14 days isolation period, in the city of Delhi, India. Through a survey conducted telephonically, participants self reported on six major mental health indicators: levels of worry, mood, lifestyle changes made through the phase of diagnosis and recovery, perceived discrimination faced due to the diagnosis, and the willingness to donate blood plasma. Descriptive findings show lower levels of worry than at the time of testing and diagnosis, positive mood states, and availability of social support. One Way Anova results further indicate that worry differed significantly across groups with differences in lifestyle changes, reported mood, availability of medical care, and the willingness to donate plasma. These findings contribute toward an informed understanding about recovery from coronavirus and sustainable coping with the pandemic, which can aid related health initiatives and evolving policy.