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Introduction: STAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case report: A 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. Conclusion(s): To our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.Copyright © 2023 Elsevier Inc.
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Introduction: Midazolam based continuous iv sedation became again prominent during the COVID-19 pandemic. However, this sedation therapy is associated with a high incidence of benzodiazepine-related delirium and an increased number of days spent in coma. Given the high midazolam dose requirements in some patients and due to the renal clearance (CL) of the active metabolite 1-OH-midazolam-glucuronide (OHmidazolamGluc), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) may are at risk of prolonged sedation. Therefore, the aim of the study was to investigate the CL of midazolam and metabolites in 5 critically ill COVID-19 patients with CRRT. Method(s): Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam (OHmidazolam) and OHmidazolamGluc plasma samples were analysed by an UPLCMS/ MS method. CL of midazolam and metabolites were calculated by the delivered renal dose and sieving (SC) coefficient. Subsequently, the CL and delivered renal dose were corrected for downtime therapy and filter integrity by a filter urea ratio. Result(s): We included 4 cases of CVVHD and 2 cases of CVVHDF. Midazolam, OHmidazolam and OHmidazolamGluc concentrations in mug/l ranged from 0 to 6070, 0 to 295 and 1727 to 39,000, respectively. SCs ranged from 0.02 to 0.03 for midazolam, 0.05 to 0.06 for OHmidazolam and 0.23-0.43 for OHmidazolamGluc. The CL in ml/min by the delivered renal dose was 0.82-1.67 for midazolam, 2.20-3.46 for OHmidazolam and 4.0-27.65 for OHmidazolamGluc. The CL in ml/min by the corrected renal dose was 0.68-1.50, 1.83-2.33 and 3.40-25.4, respectively. The urea ratios were 0.53 to 1.0. Conclusion(s): Midazolam and OHmidazolam are not removed efficiently by CRRT and OHmidazolamGluc approximately up to 43%. Type of CRRT, filter integrity and downtime of CRRT affect the CL of midazolam and metabolites. Our results have implications for more personalized titration of midazolam in COVID-19 patients with CRRT, mainly to avoid oversedation.
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The N protein of the SARS-CoV-2 virion is critical for viral genome packaging via RNA binding and regulation of viral transcription at the replication-transcription complex (RTC). The N protein can be divided into five main domains, and the central region is the linker, which is predicted to be primarily disordered and has not been heavily studied. The linker is Serine-Arginine Rich, which is phosphorylated at multiple sites by host kinases during infection, thereby promoting the N protein's role in viral transcription. Phosphorylation is a critical process for the regulation of many cellular processes and can provide recognition sites for binding complexes. In a study that examined the recognition of the SARS-CoV-2 N protein by the human 14-3-3 protein, the linker was found to contain critical phosphosites for 14-3-3 binding. The goals of this project are to determine the structure, dynamics, and RNA interactions of the Serine-Arginine Rich linker region. To accomplish this, we performed Nuclear Magnetic Resonance spectroscopy (NMR) experiments to analyze the structure of the linker region of the N protein and its ability to bind viral RNA. NMR confirms predictions that the linker is not entirely unstructured and it is able to bind RNA. The linker region of the N protein with phosphoserine incorporated at S188 was also examined via an NMR titration experiment with 1-1000 RNA. Compared to wild type, the incorporation of phosphorylation decreases binding. Other biophysical techniques such as Analytical Ultracentrifugation (AUC) and Multi-Angle Light Scattering (MALS) are used to identify the association state of the linker and the size of the resulting protein-RNA complex. We are currently working to biophysically characterize the structure, dynamics, and viral RNA binding ability of a mutation found in the Delta and Omicron variants: the R203M linker, which have been shown to enhance viral infectivity. This work was supported by the NSF EAGER grant NSF/ MCB 2034446 and URSA Engage. Support to facilities includes the Oregon State University NMR Facility funded in part by NIH, HEI Grant 1S10OD018518, and by the M. J. Murdock Charitable Trust grant # 2014162.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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Background: The rapid emergence of the SARS-CoV-2 Omicron variant that evades many therapies illustrates the need for antiviral treatments with high genetic barriers to resistance. The small molecule PAV-104, identified through a moderate-throughput screen involving cell-free protein synthesis, was recently shown to target a subset of host protein assembly machinery in a manner specific to viral assembly with minimal host toxicity. The chemotype shows broad activity against respiratory viral pathogens, including Orthomyxoviridae, Paramyxoviridae, Adenoviridae, Herpesviridae, and Picornaviridae, with low susceptibility to evolutionary escape. Here, we investigated the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). Method(s): Dose-dependent cytotoxicity of PAV-104 in Calu-3 cells was determined by MTT assay. Calu-3 cells were infected with SARS-CoV-2 isolate USA-WA1/2020 (MOI=0.01). Primary AECs were isolated from healthy donor lung transplant tissue, cultured at air liquid interface (ALI), and infected with SARS-CoV-2 Gamma, Delta, and Omicron variants (MOI=0.1). SARS-CoV-2 replication was assessed by RT-PCR quantitation of the N gene, immunofluorescence assay (IFA) of nucleocapsid (N) protein, and titration of supernatant (TCID50). Transient co-expression of four SARS-CoV-2 structural proteins (N, M, S, E) to produce virus-like particles (VLPs) was used to study the effect of PAV-104 on viral assembly. Drug resin affinity chromatography was performed to study the interaction between PAV-104 and N. Glycerol gradient sedimentation was used to assess N oligomerization. Total RNA-seq and the REACTOME database were used to evaluate PAV-104 effects on the host transcriptome. Result(s): PAV-104 reached 50% cytotoxicity in Calu-3 cells at 3732 nM (Fig.1A). 50 nM PAV-104 inhibited >99% of SARS-CoV-2 infection in Calu-3 cells (p< 0.01) and in primary AECs (p< 0.01) (Fig.1B-E). PAV-104 specifically inhibited SARS-CoV-2 post entry, and suppressed production of SARS-CoV-2 VLPs without affecting viral protein synthesis. PAV-104 interacted with SARS-CoV-2 N and interfered with N oligomerization. Transcriptome analysis revealed that PAV-104 treatment reversed SARS-CoV-2 induction of the interferon and maturation of nucleoprotein signaling pathways. Conclusion(s): PAV-104 is a pan-respiratory virus small molecule inhibitor with promising activity against SARS-CoV-2 in human airway epithelial cells that should be explored in animal models and clinical studies.
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Background: Metformin has in vitro activity against SARS-CoV-2. In a published phase 3, quadruple-blinded, placebo-controlled randomized trial of outpatient COVID-19 therapy, metformin resulted in a 42% reduction in ER visits/hospitalizations/deaths by day 14, 58% reduction in hospitalizations/ death by day 28, and 42% reduction in Long Covid through 10 months. This analysis presents the results of viral load sampling performed during that clinical trial. Method(s): Covid-Out trial (NCT04510194) enrolled adults aged 30 to 85 within 3 days of a documented SARS-CoV-2 infection and < 7 days after symptom onset. The trial randomized 1323 participants to metformin (1000mg/day days 2-5;1500mg/day days 6 to 14), ivermectin, fluvoxamine, and/or exact-matching placebo in a 2x3 factorial trial design. Nasal swabs for viral load were an optional component, self-collected from the anterior nares on day 1, 5, and 10. Viral loads were measured via RT-qPCR using N1 and N2 targets in the SARSCoV- 2 nucleocapsid protein, with relative Ct values converted to absolute copy number via calibration to droplet digital PCR. A linear Tobit regression model was used to assess change over time while accounting for left censoring due to the viral load limit of detection. Results were adjusted for other treatment allocations within the factorial design, vaccination status, and baseline viral load. Repeated measures were accounted for using clustered standard errors within participants. Result(s): Samples were available from n = 945, 871, and 775 participants on days 1, 5, and 10, respectively. The mean change from baseline to followup was -0.64 log10 copies/mL (95%CI, -1.16 to -0.13) for metformin versus placebo, which equates to a 4.4-fold greater decrease. The mean change in SARS-CoV-2 from baseline to day 5 was -0.48 log10 copies/mL, and was -0.81 log10 copies/mL from baseline to day 10. The anti-viral effect increased with increased metformin dosing days 6-14. The antiviral effect was larger in those unvaccinated (mean -0.95 log copies/mL) than vaccinated (mean -0.39 log copies/mL). There was no change in viral load vs. placebo for ivermectin or fluvoxamine. Conclusion(s): Metformin lowered SARS-CoV-2 viral load in this quadrupleblinded, randomized clinical trial. The temporal relationship to dose titration suggests a dose-dependent effect. The magnitude of antiviral effect was similar to nirmatrelvir at day 5, greater than nirmatrelvir at day 10. Metformin is safe, widely available, and has few contraindications.
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Annotation: The causes of the development of cerebrovascular diseases in COVID-19 may be a significant deterioration in the rheological properties of blood, activation of hemostasis, changes in the atrombogenic properties of the vascular wall endothelium. Thrombocytopenia and elevated levels of fibrinogen, D-dimer and coagulation factor VIII are most often observed in COVID-19, Changes in the indicators of neurobiomarkers, namely antibodies to gliadin- fibrillar acid protein (GFAP), S-100 protein, to serotonin and dopamine receptors in CHEM indicate the severity of this disease. The aim of the study was to study the features of neurological and biochemical parameters in patients with CHEM who had a coronavirus infection, to assess the number and prognostic value of markers of brain damage: antibodies to GFAP, serotonin, dopamine receptors and S-100 protein.
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Background Management of pediatric pulmonary hypertension (PH) may require manipulation of multiple receptor sites to maximize response to medical therapy. Assessment of response typically occurs through imaging, labs, physical exam and recurrent cardiac catheterization, with anesthetic exposure to assess pulmonary artery pressures (PAP) and vascular resistance (PVR). We aimed to assess feasibility, safety and utility of remote PAP monitoring in pediatric PH patients. Methods We reviewed 4 pediatric patients with significant PH, each of whom underwent cardiac catheterization with pulmonary vasoreactivity testing and placement of a CardioMEMS remote PAP monitoring device. Results Four patients (P1-4: ages 5, 6, 8 and 10 years old) underwent CardioMEMS insertion without procedural complication. P1, P2 and P3 presented with unrepaired VSD;ASD with partial anomalous pulmonary venous return;and ASD and PDA, respectively, while P4 had prior repair of atrioventricular canal. Three patients had Down syndrome. All had elevated PAP and PVR. Mean left lower PA branch size was 7 mm. Mean PAP prior to therapy was 70 mm Hg for P1, 82 for P2, 93 for P3 and 30 for P4. All 4 patients required initiation of triple therapy for treatment of PH, with improvement or normalization of PAP by CardioMEMS, which also included surgical or catheter based intervention for 3 patients. Post-repair of P2, he was unable to be separated from cardiopulmonary bypass and was placed on ECMO. Right ventricular cardiac output improved over 2 weeks, with improvement of PAP determined through serial CardioMEMS. He was successfully decannulated, utilizing CardioMEMS in the OR. Two patients also developed COVID respiratory infections at home with CardioMEMS assessments allowing for oxygen and medication titration. Conclusion Remote PAP monitoring is feasible and appears safe in pediatric patients with adequate PA size. It allows for manipulation of medical therapy with real time knowledge of impact on PAP and can augment management during weaning of mechanical cardiac support. It may also augment decision-making in management of PH patients with developmental disabilities in whom traditional assessments may be more challenging.Copyright © 2023 American College of Cardiology Foundation
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Background: SARS-CoV2 pneumonia with respiratory failure may evolve to ARDS. The effects of high PEEP on respiratory compliance varies in different patients. Our study is based on the high accurancy and sensitivity of Lung Ultrasound (LUS) in evaluating the heterogeneous distribution of aeration loss, and use of LUS to individualize PEEP titration to produce the best lung aeration. Method(s): Retrospective trial on two cohorts of patients (15+15) with SARS-CoV2 ARDS mild-to-moderate(according to Berlin Criteria), aged 18 to 80 y.o. In Group I(GI) PEEP titration was LUS guided, in Group II(GII) titration was SpO2-guided. In GI LUS score was calculated dividing lungs in six regions per hemithorax. Patients were treated with NIV or CPAP Helmet. In GII FiO2 was initially set at 40% and increased if target oxygenation was not met. In GI PEEP was set at 5 cmH2O and guided by LUS aeration. Cases were managed by PEEP values from 7.5-15 cmH2O. Determination of optimal PaO2/FiO2 was the primary outcome. Secondary outcomes were adverse event: incidence of barotrauma/pneumothorax/pneumomediastinum, haemodynamics (MAP and HR), time spent on NIV/ CPAP, length of stay, weaning categories, and mortality at day 28. Result(s): P/F ratio was 282+/-38.6 in GI, and 243+/-43.2 in GII. We didn't detect significant statistical differences between the two groups in terms of mortality (6.2% in Gi vs 6.8% in GII) nor in time to weaning (5+/-6 in GI vs 16+/-4.5 in GII). In-stead there were fewer AE in GI vs GII. Length of stay was reduced with mean value of 4.3 days. Conclusion(s): Compared to SpO2-guided PEEP titration, LUS-based titration was associated with favorable effects on rate of adverse events and length of hospital stay.
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Background and Aims: The burden of uncontrolled DM amongst insulin users in Malaysia is great. Structured Self- Monitoring of Blood Glucose (SMBG) that are stored in cloud, simplified into visual charts, graphs coupled with a diabetes management system (DMS) that allows remote insulin titration can lead to improvement of glycemic control. Method(s): 124 Type 2 DM outpatients with HbA1C > 8% on intensive insulin therapy were recruited in this 26 weeks, multicenter, double arm, randomized controlled study. The patients were randomized to control arm which used traditional logbook and intervention arm which received remote insulin titration with a Bluetooth glucometer coupled with a DMS. The primary objective was to compare reduction of HbA1C and the secondary objective was to compare the change in Diabetes Distress Scale (DDS) between the control and intervention arm. Result(s): There was significantly higher mean reduction of HbA1C in the intervention group ;-2.016+/-1.60 versus - 1.326+/-1.51 in the control group (p = 0.027) by week 14 and was maintained till Week 26. There was no significant difference between the reduction of DDS between both groups. The mean frequency of SMBG in the intervention group was significantly higher than the control group;339.656+/-171.14 (intervention) versus 216.716+/-96.40 (control) [p < 0.001]. Conclusion(s): Remote insulin titration has been proven effective especially during COVID-19 whereby there was imminent need for reduction of physical visits to the hospital. This has led to improvement of glycemic control but could translate to lesser waiting time and reduction of cost in the long term.
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Introduction: Continuous positive airway pressure (CPAP) titration was dramatically affected by the coronavirus disease 2019 pandemic due to increased biological risk. This study aims to compare successful CPAP adaptation and compliance with home telemedicine CPAP titration with the usual method based on face-to-face visits. Methodology: A prospective cohort using telemedicine home-CPAP titration and follow-up during the COVID-19 pandemic (TC) was compared with a retrospective cohort receiving face-to-face pre-pandemic home titration (RC). The TC included a subgroup with a smartphone application (APP). Successful CPAP adaptation and compliance at one month of follow-up were the main endpoints, while patient satisfaction and costs were secondary endpoints. Result(s): 210 consecutive patients were evaluated (80 RC, 130 TC). 36 patients used APP (TC-APP). CPAP titration was successful in 90% in RC vs 95% in TC (p-value 0.346) and 100% in TC-APP (p-value 0.222). No differences between groups were found at one month of compliance (4.79 h/d RC, 4.33 h/d TC, 4.59 h/d TC-APP). Patient satisfaction out of 10 was 7.69 (SD 2.05) in RC versus 9.02 (SD 0.64) in TC (p-value <0.001). 64% of the TC-APP subgroup reported that their telemedicine strategy influenced in an increase in CPAP use (p-value 0.011). CPAP adaptation with follow-up had an estimated direct staff cost per patient of 19.61 (SD 8.61) in TC-noAPP (TC no APP used) against 23.79 (SD 9.94) in TC-APP (p-value 0.048). Conclusion(s): Telemedicine in CPAP titration and early follow-up is equivalent to the usual care in terms of successfully adaption and compliance, while achieving a greater patient satisfaction.
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Introduction: Covid-19 epidemic results from an infection caused by SARS-CoV2. Evolution-based analyses on the nucleotide sequences show that SARS-CoV2 is a member of the genus Beta-coronaviruses and its genome consists of a single-stranded RNA, encoding 16 proteins. Among the structural proteins, the nucleocapsid is the most abundant protein in virus structure, highly immunogenic, with sequence conservatory. Due to a large number of mutations in the spike protein, the aim of this study was to investigate bioinformatics, expression of nucleocapsid protein and evaluate its immunogenicity as an immunogenic candidate Material(s) and Method(s): B and T cell epitopes of nucleocapsid protein were examined in the IEDB database. The PET28a-N plasmid was transferred to E. coli BL21(DE3) expression host, and IPTG induced recombinant protein expression. The protein was purified using Ni-NTA column affinity chromatography, and the Western blotting method was utilized to confirm it. Finally, mice were immunized with three routes of purified protein. Statistical analysis of the control group injection and test results was carried out by t-test from SPSS software. Result(s): The optimized gene had a Codon adaptation index (CAI) of 0/97 Percentage of codons having high-frequency distribution was improved to 85%. Expression of recombinant protein in E.coli led to the production of BoNT/B-HCC with a molecular weight of 45 kDa. The total yield of purified protein was 43 mg/L. Immunization of mice induced serum antibody response. Statistical analysis showed that the antibody titer ratio was significantly different compared to the control sample and the antibody titer was acceptable up to a dilution of 1.256000 Conclusion(s): According to the present study results, the protein can be used as an immunogenic candidate for developing vaccines against SARS-CoV2 in future research.Copyright © 2022, Semnan University of Medical Sciences. All rights reserved.
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Introduction: Covid-19 epidemic results from an infection caused by SARS-CoV2. Evolution-based analyses on the nucleotide sequences show that SARS-CoV2 is a member of the genus Beta-coronaviruses and its genome consists of a single-stranded RNA, encoding 16 proteins. Among the structural proteins, the nucleocapsid is the most abundant protein in virus structure, highly immunogenic, with sequence conservatory. Due to a large number of mutations in the spike protein, the aim of this study was to investigate bioinformatics, expression of nucleocapsid protein and evaluate its immunogenicity as an immunogenic candidate Material(s) and Method(s): B and T cell epitopes of nucleocapsid protein were examined in the IEDB database. The PET28a-N plasmid was transferred to E. coli BL21(DE3) expression host, and IPTG induced recombinant protein expression. The protein was purified using Ni-NTA column affinity chromatography, and the Western blotting method was utilized to confirm it. Finally, mice were immunized with three routes of purified protein. Statistical analysis of the control group injection and test results was carried out by t-test from SPSS software. Result(s): The optimized gene had a Codon adaptation index (CAI) of 0/97 Percentage of codons having high-frequency distribution was improved to 85%. Expression of recombinant protein in E.coli led to the production of BoNT/B-HCC with a molecular weight of 45 kDa. The total yield of purified protein was 43 mg/L. Immunization of mice induced serum antibody response. Statistical analysis showed that the antibody titer ratio was significantly different compared to the control sample and the antibody titer was acceptable up to a dilution of 1.256000 Conclusion(s): According to the present study results, the protein can be used as an immunogenic candidate for developing vaccines against SARS-CoV2 in future research.Copyright © 2022, Semnan University of Medical Sciences. All rights reserved.
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Objective: Main issues in the treatment of hypertension are the low level of blood pressure (BP) control and the economic burden for health care systems. Mobile application with telemonitoring of BP could contribute to better control and lower costs by reducing office visits. This could be useful nowadays with difficult access to health system due to covid-19. The purpose of this study was to investigate if an innovative management strategy of hypertension, such as the use of ESH care application for smartphones combined with a dedicated platform, could improve hypertension control and replace frequent office visits. Design and method: 30 uncontrolled hypertensive patients, treated or untreated [mean age 53 ± 9 years, mean office BP (OBP) 146.3 ± 6.2 / 92.5 ± 9 mmHg, 53% men, 33% smokers, 23% with hypercholesterolemia] were randomized to the application assisted strategy (AAS) (17 patients), where a mobile phone application was offered to communicate home BP measurements (HBPm), or to regular office visits (13 patients). Patients BP measurements (HBPm for AAS and OBP for standard care group) were evaluated in 1 and 3 months with treatment titration if uncontrolled. In all patients OBP and ambulatory BP measurement (ABPM) were evaluated in 6 months. Results: In both groups the reduction in OBP and ABPM was significant in 6 months. In the AAS group the reduction in systolic/diastolic OBP and 24 h systolic/ diastolic BP in 6 months was -26.5 ± 5.6 / -19.4 ± 8.2 mmHg (p < 0,001) and -19.6 ± 7.7 / -13.8 ± 4.8 mmHg (p < 0.001), respectively. In the standard care group, the reduction in systolic/diastolic OBP and 24 h systolic/diastolic BP in 6 months was -22.6 ± 9.7 / -9.6 ± 11 mmHg (p < 0.005) and -18.4 ± 6.0 / - 8.8 ± 4.4 mmHg (p < 0.001). In AAS group compared to standard care group there was a greater reduction in 24 h diastolic BP (-13.8 ± 4.8 mmHg vs -8.8 ± 4.4 mmHg, p = 0.016) and in diastolic OBP (-19.4 ± 8.2 mmHg vs -9.6 ± 11.0 mmHg, p = 0.04). Conclusions: The present results indicate that the monitoring of patients through a mobile health tool could be useful in hypertension management as it is correlated with better BP control compared to office visits. The trial is still enrolling patients.
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Interferons (IFN) have antiviral activity against many viruses, including SARS-CoV-2. A combination of IFN-a2b and the antioxidant taurine is widely used in the Russian Federation, and its antiviral activity has not been studied before. The aim of this study was to determine the antiviral activity of interferon drugs, in combination with taurine and without it. The study included cytotoxicity and antiviral activity assays of IFN-a2b preparations, when stored according to the instructions at 2-8°C, and after 1 month storage at the temperature of 20-26°C in a pre-opened state. The combination of IFN alpha-2b with taurine has a higher antiviral activity compared to IFN alpha-2b mono-preparation by more than 25% at a «low» and 85% at a «high» multiplicity of infection. Selectivity index for combinations of IFN-a2b (50,000 IU/dose) + taurine (1 mg/ml) and IFN-a2b (10,000 IU/ml) + taurine (0.8 mg/ml) was more than 600 units, whereas for the IFN-a2b (10,000 IU/ml) it was 200 units. Antiviral activity does not change after one month at room temperature. The combination of interferon with taurine at high concentrations was less toxic than interferon. The results obtained demonstrate practicability of interferon alpha-2b and taurine combination use for treatment and prevention of COVID-19.
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Introduction: The bispectral index monitors the unawareness component of balanced anaesthesia and gives us the depth of Anesthesia.It reflects the response of the brain to a variety of hypnotic and inhaled anaesthesia agents. The aim of this study was to see the effect of different MAC values of isoflurane on the bispectral index and hemodynamic variations at different MAC values. Material(s) and Method(s): This prospective study was conducted on 20 patients at tertiary care center for 6 months. After induction of Anesthesia, following parameters were recorded: noninvasive blood pressure measurement, heart rate, oxygen saturation, ETCo2 and BIS values. The BIS was continuously monitored and when the MAC values of isoflurane were 0.5, 0.7, 1, 1.2 and 1.5 corresponding BIS values and all the other haemodynamic parameters were noted. Result(s): In 11 patients out of 20 patients satisfactory BIS of 40-60 was achieved at MAC 0.5. In 16 out of 20 patients satisfactory BIS 40-60 was achieved at 0.7 MAC. In all the 20 patients satisfactory BIS was achieved at 1 MAC.In 2 out of 20 patients we couldn't proceed beyond 1.0 MAC because of the fall in MAP to <65mm of Hg. In 4 out of 20 patients we couldn't proceed beyond 1.2MAC because of the fall in MAP to <65mm of Hg. Conclusion(s): Isoflurane produced satisfactory BIS of 40-60 in 16 patients at 0.7 MAC and in all the 20 patients at 1 MAC.Use of BIS in our study helped in better titration of Isoflurane according to patient's individual needs thereby we avoided light plane of anaesthesia or deep hypnosis and the adverse effects associated with it. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.
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Introduction and Objective: Idiopathic inflammatory myopathies(IIMs) is a group of autoimmune disease characterized by muscular and extra-muscular manifestation. IIMs with anti-MDA5 antibody positivity carries poor prognosis due to rapid progressive interstitial lung disease (RP-ILD). We report clinical course of patients cared in our centre. Method(s): Patients medical record were reviewed for data collection. Result(s): Four patients with MDA5 antibody positive IIMs following up in our clinic (Table 1). None has reported Covid infection. Two has respiratory disease responded to induction therapy. One still undergoing titration of immunosuppressant. One female patient presented unwell with pleural effusion and acute pneumonitis. Patient later developed rapid progression of interstitial lung inflammation with refractory supraventricular tachycardia. IVIG was initiated, however she succumbed to adult respiratory distress syndrome (ARDS) due to pneumonia. Plasma exchange was not carried out due to source limitation at that time of period. Conclusion(s): Prevalence of anti MDA-5 positive is 30%-50% in Asians patients with IIMs particularly the east. However, it is likely under-reported in Malaysia due to lack of understanding of the pattern of disease in our multiracial population as well as lack of myositis serology tests availability especially in government hospitals. Research and registry should be instituted to allow better study of this disease in our population, to better the treatment and reduce morbidity and mortality due to rapid progressing interstitial lung disease. (Table Presented).
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Introduction: At the outset of the COVID-19 pandemic we observed an unacceptably high incidence of intracranial hemorrhage during VV ECMO support for COVID-19 related respiratory failure. The relationship between PTT and Anti-Xa values was explored by pharmacy and facility ECMO leadership, and found COVID patients to have elevated Anti-Xa levels at prescribed PTT levels. Method(s): We retrospectively analyzed data of 38 adult COVID-19 VV ECMO patients at Massachusetts General Hospital from March 18, 2020 to February 1, 2022 for incidence of ICH before and after anticoagulation protocol was changed on May 12th 2020. Result(s): Prior to change in practice, ICH was present in 33% (n = 4) of all COVID+ VV ECMO runs (n = 12). ICH was present in 57% of all deaths (n = 7) during this period. On May 12th 2020, after a pharmacy review, along with regional/international meetings among many ECMO centers MGH initiated a new protocol for COVID-19 positive ECMO patients targeting an Anti-Xa range of 0.15-0.29 with heparin titration. After this change, there were a subsequent 26 VV ECMO runs meeting the criteria for this study. ICH was present in only 3.8 % of patients (n = 1). And was present 6.3% (n = 1) of all deaths (n = 16). Conclusion(s): Anti Xa guided anticoagulation strategy resulted in a 88% decrease in the incidence of ICH in COVID-19 positive VV ECMO patients during the time of this retrospective analysis and proved a safe alternative to PTT guided heparin therapy.
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Specific clinical, electrophysiological and serological features are used to recognise a phenotype fitting the atypical chronic inflammatory demyelinating (CIDP) variant spectrum. We report a 28-year-old male patient, without any significant history apart from a recent asymptomatic COVID-19 infection, presenting at first with bilateral facial nerve palsy, subsequently -three months later- developing an subacute onset symmetric sensory ataxia and arefl exia, and thirdly experiencing diffuse rapidly progressive motor deficits. Additional investigations suggested an autoimmune polyneuropathy: Liquor analysis showed cytoalbuminologic dissociation. Cerebrospinal fluid protein elevation was remarkable: 631 mg/dL. Nerve conduction studies showed prominent distal latencies prolongation and dispersion of the potentials, meeting the electrodiagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society for CIDP (2021). Full spine magnetic resonance imaging depicted pathological thickening and enhancement of the roots of the cauda equina as seen in radiculitis. There was no or poor response to conventional treatment, i.e. immunoglobulins (IVIG), corticosteroids and even plasmapheresis. Muscle weakness deteriorated. Presence of serum IgG4 anti- contactin-1 (CNTN1) antibodies was found by ELISA identifi- cation and titration, and the patient improved substantially after rituximab treatment. While contributing to the expanding confidence in nodal and paranodal antibodies as valuable biomarkers in clinical practice, our case entails several peculiarities: 1/ SARS-CoV2 positivity as a possible trigger of this auto-immune polyneuropathy 2/ A considerably younger age of onset than in the patients already described (range 33-76 years). 3/ The clinical course progressed in an atypical manner even for atypical CIDP: Initial presentation with bilateral asymmetric facial palsy, followed by sensory ataxia, which prompted the initial diagnosis of Miller-Fisher syndrome, and later development of severe motor impairment. 4/ Proteinorachy was so pronounced that we considered neuroborreliosis as a potential associated disorder. Borrelia seroconversion occurred after the first IVIG-treatment, and could be false positive. However, the patient was treated with intravenous ceftriaxone, which had no effect on the clinic. 5/ Antibodies against CNTN1 were undetectable after 2 months of rituximab. Emphasising the both diagnostic and therapeutic importance of recognising a phenotype compatible with atypical CIDP, an underrecognized and consequently undertreated disease where early diagnosis and prevention of axonal damage is crucial in.
ABSTRACT
Introduction: There are increased rates of thrombotic events such as strokes, pulmonary embolism, cutaneous and alveolar micro-thrombosis in COVID-19 patients in intensive care.1,2 Using anti-Xa, which is a direct measure of heparin activity, for dose titration leads to a greater time in therapeutic range and fewer dose adjustments than using APTTr.3 It was considered therefore that anti-Xa would be a more accurate method for monitoring heparin dosing in COVID-19 patients. Objectives: •To analyse and compare APTTr versus anti-Xa during therapeutic heparin monitoring in critical care patients with Covid-19 •To assess compliance with a new anti-Xa heparin monitoring protocol using the following standards (expected 100%). COVID-19 positive patients in critical care prescribed heparin: 1. Must have an Anti-Xa level test 5-7 hours after starting the infusion (target 6 hours) 2. Must have the correct dose alteration in response to the Anti-Xa levels 3. Must have received an adjustment of the heparin infusion rate within 2 hours of the Anti-Xa level result Methods: From April 2020 both anti-Xa levels and APTTr were run concurrently on the same blood sample for all COVID-19 positive patients receiving therapeutic unfractionated heparin on critical care. The reference ranges used were ≥0.5 to <0.8 and ≥1.5 to <2.5 respectively. The results were mapped against the respective dosing titration protocols to determine the discrepancy rate in assessing whether levels were low, in range or high for each test. Following the implementation of a new therapeutic unfractionated heparin titration protocol, using anti-Xa instead of APTTr in COVID-19 patients, an audit was conducted in these patients to determine the adherence to the new protocol. Audit data collected retrospectively April to June 2020 inclusive from Philips and ICE. Results: Therapeutic unfractionated heparin was given to 24 Covid-19 positive patients between April and December 2020 with a total of 482 samples (mean 20 samples per treatment course). The agreement rate between anti-Xa and APTTr was 44% i.e. results were both in range, both low or both high. In 35% of the paired samples the anti-Xa was judged to be in range, whereas the APTTr result suggested a dose increase was needed. The shorter audit period highlighted 13 eligible patients (59 paired samples) on therapeutic heparin during audit period. The adherence to standards 1,2 and 3 were 67%, 98% and 95% respectively. 21 sample results were excluded from standard 3 because the time of rate adjustment or acknowledgment was not recorded. For the remainder the mean time to adjustment of infusion rate following a sample being sent was 42 minutes. Conclusion: The 56% discordance rate is higher than reported elsewhere in the literature (46-49%) potentially demonstrating the effect of COVID-19 on APTTr reliability. The high rate of disagreement between the two tests suggests that if APTTr had been used for dosing in COVID-19 patients that significantly higher rates of heparin would have been used. With respect to the audit element sample timing and documentation of result acknowledgement, regardless of whether it necessitates a change in rate or not, needs to be improved.
ABSTRACT
Introduction: Following the publication of the ARDS Network (ARDSnet) trial over two decades ago lung protective ventilation with low tidal volumes has become a mainstay in the evidence based management of acute respiratory distress syndrome (ARDS). The ARDSnet trial protocol uses the Devine formula which is based on height and gender to calculate the predicted body weight (PBW) which is then used to calculate the tidal volume in ml/kg.1-2 The first step to calculating a safe tidal volume is measuring the patient's height. Visual estimates of patient's height are often inaccurate and measurements in some patient groups can be challenging. Various methods have been suggested to aid accuracy and ease of measurement. Once the height is known the second step is to use the Devine formula to calculate the PBW. This is often done using online calculators or using tables with height and the PBW. The third and final step is multiplying the PBW by the desired tidal volume in ml/kg typically starting at 6ml/kg. During the COVID-19 pandemic, the combination of various factors such as greatly increased doctor and nursing workload, use of personal protective equipment (PPE), concerns over the use of reusable equipment such as tape measures and difficult access to online calculators for PBW calculation when donned in PPE in some COVID-19 units made measuring height and calculating a safe tidal volume particularly challenging.3 Objectives: To develop a quick, safe way of calculating lung protective tidal volumes for ARDS patients including in COVID-19 Intensive care units. Methods: We used the Devine formula to calculate the PBW in males and females at every centimeter (cm) from 152cm to 200cm. Males PBW= 50 + (0.91 × [height in centimeters -152.4]) Female PBW= 45.5 + (0.91 × [height in centimeters -152.4]). We then multiplied the PBW by 6 to generate a 6ml/kg PBW tidal volume. Using image editing software, we then designed gender specific rulers with cm markings to measure height placed beside the corresponding calculated PBW and tidal volume 6ml/kg for that height. We also placed the ARDSnet PEEP/ Fio2 titration table. The resulting ruler when printed to scale can then be used as a disposable measuring tape that allows height, PBW and 6ml/kg tidal volume to be calculated easily with one measurement and without the need to resort to calculators, tables or reusable equipment. Results: Conclusions: These JPEG images can be downloaded and printed to scale. Once printed the ARDS 'rulers' allow easy and quick measurement of height, PBW and 6ml/kg tidal volume with one measurement without resorting to calculators or tables. As they are simply printed on standard paper, they are single use and therefore do not pose an infection control risk.