To the tumor and beyond: Tales of a holistic miRNA delivery vehicle

Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of mRNA vaccines to prevent against SARS-CoV-2 and the first FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized, intramolecular molecule that achieves all of these essential features. Moreover, the ligand used to achieve successful delivery is also being evaluated for imaging tumors localized in the central nervous system. Here, the challenges we face, the hurdles we have overcome, and the barriers that still remain to achieve success in revealing the clinical potential of miRNA as anti-cancer therapeutics will be presented.

Real-World Single-Centre Experience of Jak Inhibitor Use in Ra

Background/Aims The use of Janus Kinase Inhibitors (JAKi) has been gradually increasing overtime in the management of rheumatoid arthritis (RA) and other inflammatory arthritis and these appeal to patients. being oral agents. Nevertheless, rheumatologists have become cautious about their use since recent trials have shown safety concerns about VTEs, MACE and malignancies. Methods We decided to study use of JAKi at our centre in Princess of Wales Hospital Bridgend. The aim was to assess whether appropriate patients were selected (considering cautions about MACE, VTEs and malignancies). We also wanted to see whether all patients had required pretreatment safety testing and post-treatment monitoring performed. Results These were 70 patients;59 were females and 11 were males. All of them were diagnosed as RA. Average age was 61.1 years (20-85), average duration of disease 129.9 months (16-340) and average duration of treatment was 58.1 weeks. The most common JAKi being used was baricitinib (84%) followed by tofacitinib (12%) and upadacitinib (4%). 50% patient were on concomitant csDMARDs among whom two-thirds were on methotrexate. Looking at previous biologic use, 9 patients were biologic naive, 22 had one biologic, 15 had two biologics used in the past. All patients were appropriately selected (severe RA and no significant risk factors for MACE, VTEs and malignancies). All patients had pre-treatment Hepatitis B, Hepatitis C, latent TB, FBC and LFTs checked. All patients had FBC and LFTs monitored post treatment. No patient developed VTE, MACE or cancer on treatment. 84.2% patients had lipids tested before starting JAKi. 22.8% patients had abnormal lipids before Rx initiation and 62.5% of these were on lipid lowering Rx. All patients had lipids tested post treatment, but the timing was quite variable and only 62.5% of patients had lipids tested on the recommended time. There were 2 deaths recorded in this cohort. One of those was an 80-year-old RA patient on baricitinib 2mg OD, who died due to chest infection on the background of ILD. He was not on steroids or csDMARDs. The second patient was 63 years' old (on baricitinib 4mg OD), and died due to respiratory sepsis, and was also on azathioprine. She had RA with advanced ILD. The reasons for discontinuing JAKi were inefficacy (46%), side effects (39%) and both inefficacy and side effects (15%). 41.4%of patient experienced side effects due to JAKi. These included infection 28%, deranged lipids 17%, cytopenia 14%, deranged LFTs 14%, GI side effects 10%, skin rash 7% and varicella zoster 3%. Conclusion There has been steady increase in the use of tsDMARDs for RA and other rheumatic conditions. Due to short half-life, these drugs became a popular choice during COVID-19 pandemic but on the other hand safety monitoring became extremely challenging during this time.

An Emerging Role of Interferon Targeted Therapy in Mucocutaneous Sle: A Prospective Real-World Evaluation of Anifrolumab for Refractory Cutaneous Lupus

Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300mg by monthly iv infusion) following application to the manufacturer's early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI);Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n=5, chilblain LE n=1, subacute cutaneous LE n=1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26;higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved >=75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p<0.001) and EQ5D-VAS (p=0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p=0.01) and pain (p=0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients.

Rising level of pulmonary dioxin might trigger CMV and HSV-1 reactivation via bHLH/PAS/AhR:ARNT transcription pathway in lungs of immunocompetent COVID-19 patients with ARDS

Study objective. It has been shown that human common viruses are new target genes for host cell dioxin receptor transcriptional (AhR-ARNT) complex initially proven to up-regulate mammalian genes containing dioxin-response elements (DRE) in the promoters [doi:10.1016/j.ijid.2012.05.265]. Initially, transactivation of HIV-1 and HBV by 2,3,7,8-tetrachlodibenzop- dioxin (TCDD) at low nanomolar range was demonstrated [doi:10.3109/00498259309057034]. Noteworthy, transactivation of human cytomegalovirus (CMV) was shown with 0.3 ppt dioxin, i.e. lower than its current background level in the general population (~3.0 ppt). Recently, reactivation of CMV infection was found to influence worse clinical outcome following SARS-CoV-2 infection (doi: 10.1186/s12979-020- 00185-x). Other findings showed that CMV and herpes simplex virus 1 (HSV-1) reactivation were observed in immunocompetent patients with COVID-19 acute respiratory distress syndrome (ARDS) (doi.org/10.1186/s13054-020-03252-3). Addressing occurrence of Herpesviridae reactivation in severe COVID-19 patients, and still unspecified real triggers of CMV and HSV-1 reactivations, we tested TCDD, which current body burden (DBB) ranges from 20 pg/g (TEQ in fat) in general population to 100 pg/g in older people. Methods. In Silico quantitation of active DRE in promoters of viral genes. Virus DNA hybridization assay. Clinical and epidemiological analyses. Results and Discussion. In this study, a computational search for DRE in CMV and HSV-1 genes was performed by SITECON, a tool recognizing potentially active transcriptional factor binding sites. In silico analysis revealed in regulatory region of CMV IE genes from 5 to 10 DRE, and from 6 to 8 DRE in regulatory region of HSV-1 IE genes.We established that a low picomolar TCDD can trigger up-regulation of CMV and HSV-1 genes via AhR:Arnt transcription factor in macrophage(doi.org/10.1016/ j.ijid.2012.05.265) and glial human cell lines (doi.org/10.1016/j. jalz.2016.06.1268), respectively. In fact, viral reactivation may be triggered in COVID-19 ARDS patients by higher pulmonary TCDD concentrations, because "lipid storm" within lungs of severe COVID-19 patients has been recently reported (doi.org/ 10.1101/2020.12.04.20242115). TCDD is known as the most potent xenobiotic, which bioaccumulates and has estimation half-life in humans of up to 10 yr. Due to hydrophobic character (Log P octanol/water: 7.05), TCDD partitions into inflammatory lipids in lung tissue thus augmenting its local concentration. Population-based epidemiological data on SARS-CoV-2 first wave of pandemic revealed high level of CMV seropositivity and cumulative mortality rate 4.5 times in Lombardi region of Italy, where after Seveso industrial accident TCDD plasma level in pre-exposed subjects is 15 times the level in rest of Italy (doi. org/10.3389/fpubh.2020.620416). Also, Arctic Native (AN) peoples consume dioxin-contaminated fat in seafood and have TCDD DBB, i.e. 7 times that in general population. To the point of this paper, their COVID-19 mortality is 2.2 times of that among non-AN Alaskans (doi: 10.15585/mmwr.mm6949a3). Conclusion(s): TCDD in the picomolar range may trigger CMV expression in lung cells and commit virus to the lytic cycle, which can be applied to reactivation of Herpesviridae infection in immunocompetent patients with COVID-19 ARDS syndrome.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Safety and Pharmacokinetics of a Novel Double Prodrug Asc10 in Healthy Subjects

Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.

Pharmacokinetics Informs Remdesivir Dosing for Patients with Severe Renal Impairment

Background: Despite renal impairment (RI) being a risk factor for severe COVID-19, there are no approved antiviral treatment options for patients with severely impaired kidney function (eGFR less than 30 mL/min/1.73 m2 or kidney failure) in the US. At the time remdesivir (RDV) was initially approved for the treatment of COVID-19, the impact of renal impairment (RI) on pharmacokinetics (PK) of RDV, its metabolites, and the excipient, sulfobutylether beta-cyclodextrin sodium (SBECD), was not known. Method(s): Here, we report the PK data supporting dosing of RDV in COVID-19 patients with severely impaired kidney function. PK samples for RDV and metabolites (GS-704277, GS-441524) were collected in the Phase 3 REDPINE study in hospitalized COVID-19 patients with severely impaired kidney function. Participants in this double-blind study were randomized 2:1 to intravenous (IV) remdesivir (200 mg on Day 1, then 100 mg daily up to Day 5) or IV saline as placebo-to-match. SBECD PK was analyzed in a phase 1 study in non-COVID-19 participants with normal kidney function, mild and moderate RI who received 100 mg dose of remdesivir (containing 3000 mg SBECD). The population PK analysis included observations from healthy and COVID-19 patients with full range of renal function across all adult studies. Result(s): Geometric mean exposures (AUCtau) observed in REDPINE Study as compared to PINETREE Study increased up to 553% for the GS-441524 metabolite (dependent on renal elimination) and to a lesser degree GS-704277 (294%, minor renal elimination) and RDV (78.9%;an increase explained by factors other than renal function, namely, hospitalization and body weight) (Table 1). The increased PK exposures were not associated with new safety signals in this study (n=163 remdesivir, n=80 placebo). Population PK analysis identified baseline eGFR as a significant covariate for GS-704277 and GS-441524 clearance, but not for RDV itself. SBECD PK was characterized by short half-life (t1/2) (1.6 hours in normal renal function to 3.8 hours in moderate RI) and fast plasma clearance (7.9 L/h in normal renal function). Analysis of SBECD in severe RI (REDPINE) is ongoing, but accumulation is not expected based on its observed short plasma t1/2. Conclusion(s): Given the observed PK and the absence of any new safety signals associated with increased metabolite levels in patients with severely impaired kidney function, no dose adjustment is recommended for RDV in COVID-19 patients with eGFR < 30 mL/min/1.73 m2, regardless of the need for dialysis.

Appendicular flap transposition in case of the left ureters defects

Introduction & Objectives: The frequency of involvement in the oncological process of the ureters in case of pelvis tumors ranges from 15 to 20%. The use of the appendix as a plastic material for the reconstruction of extended ureteral defects (EUD), including left-sided ones, remains debatable. The main goal of this study is evaluating the clinical and functional results after EUD repair using patchy transposition of the appendix. Material(s) and Method(s): Since August 2019 to June 2021, 8 laparoscopic surgeries were performed to replace the EUD using flap transposition of the appendix. Of these, 6 on the left (75%), 2 on the right (25%). 7 women (87.5%) and 1 man (12.5%) were operated on. Mean age 53+/-10.6 years. Average BMI 25.9 kg/m2. Etiology EUD: 25% radiotherapy (n2), 50% iatrogenic surgery (n4), 12.5% (n1) primary ureteral cancer, 12.5% (n1) non-Hodgkin's lymphoma. In all cases, the first stage was a wide mobilization of the ileocecal angle, the appendix was disconnected with a 45 mm hardware suture, in case of left-sided lesion, the appendix was moved isoperistaltically under the mesentery of the sigmoid colon to the left side after preliminary maximum mobilization of the process on the vascular pedicle in the form of a "triangle". All patients received a 7Fr ureteral stent. CT urography was performed on the 3rd, 7th, 11th days. Dynamic nephroscintigraphy was performed on the 90th day. Result(s): The average length of diastasis is 4.6+/-1.7 cm. The average length of the mobilized appendix was 8+/-1.8 cm. Replacement of the ureter with an appendix and a flap of the bladder according to the Demel method was performed in 1 case (12.5%), according to the Boari method in 1 case (12.5%), in 6 (75%) cases an anastomosis was formed according to the "end-to-end" type. the end". The average duration of the operation was 251+/-40.9 min, blood loss was 121+/-56.7 ml. Median removal of the ureteral stent was 36+/-18.28 days. Duration of hospital stay was 14+/-5.2 days. Median follow-up 10+/-5.3 months. Early complications (<30 days): 2 cases of urinary edema (Clavien-Dindo II), 2 cases of ipsilateral hydronephrosis (Clavien-Dindo I-II). Late complications (>30 days): 1 case of partial failure of ureterocystoanastomosis against the background of Sars-Cov-2 infection (Clavien-Dindo IIIa), 1 case of non-functioning left kidney (Clavien-Dindo IVa). Dynamic nephroscintigraphy was performed in 68.4% of patients, the average isotope accumulation time was 4.23+/-0.25 minutes, the duration of the half-life was 14.26+/-0.52 minutes. Conclusion(s): Flap transposition with the appendix is a technically difficult but possible option for extended ureteral strictures. However, various pathological processes that have developed against the background of previous treatment potentially increase the risk of developing repeated strictures or anastomotic leaks. Therefore, given the small sample of patients, further research on this issue is required.Copyright © 2023.

The Potential Impact of Ayurvedic Traditional Bhasma on SARS-CoV-2-Induced Pathogenesis

The mass casualties caused by the delta variant and the wave of the newer "Omicron" variant of SARS-COV-2 in India have brought about great concern among healthcare officials. The government and healthcare agencies are seeking effective strategies to counter the pandemic. The application of nanotechnology and repurposing of drugs are reported as promising approaches in the management of COVID-19 disease. It has also immensely boomed the search for productive, re-liable, cost-effective, and bio-assimilable alternative solutions. Since ancient times, the traditional-ly employed Ayurvedic bhasmas have been used for diverse infectious diseases, which are now employed as nanomedicine that could be applied for managing COVID-19-related health anomalies. Like currently engineered metal nanoparticles (NPs), the bhasma nanoparticles (BNPs) are also packed with unique physicochemical properties, including multi-elemental nanocrystalline compo-sition, size, shape, dissolution, surface charge, hydrophobicity, and multi-pathway regulatory as well as modulatory effects. Because of these conformational and configurational-based physico-chemical advantages, Bhasma NPs may have promising potential to manage the COVID-19 pandemic and reduce the incidence of pneumonia-like common lung infections in children as well as age-related inflammatory diseases via immunomodulatory, anti-inflammatory, antiviral, and adju-vant-related properties.Copyright © 2023 Bentham Science Publishers.

Nanotechnology Advancements in the Diagnosis and Prevention of COVID-19: Past and Future

Since the start of the decade, the coronavirus disease 2019 [COVID-19] pandemic has disrupted the world's healthcare system. Scientists have been engaged to bring about a therapeutic agent to help combat the dreaded disease. Many researchers have shown antivirals such as Remde-sivir and Favipiravir to be effective in the treatment;however, these drugs have a short half-life. Hence, the need for a drug delivery system that could prolong or alter their effect by increasing the potency of antivirals or vaccines has been proposed. Nanotechnology has always been at the fore-front of developing and diagnosing diseases. The idea of which can be borrowed to treat the novel coronavirus. The applicability needs to be vast as the disease has spread, and a fast, reliable, effective therapeutic and diagnostic procedure is the need of the hour. Emphasis on nanotechnology us-age through the intranasal and pulmonary route has been given and various applications have also been discussed in this review.Copyright © 2021 Bentham Science Publishers.

Relationship between Pain, Physical Activity, and Quality of Life in Patients with Haemophilia a and Haemophilia B

Introduction: The extended half-life (EHL) registry was established in 2016 to ascertain the long-term outcomes in patients with HaemophiliaA(HA) and B(HB) receiving replacement therapy. The aim was to quantify disease burden and quality of life at baseline and after switching to EHLs. Method(s): The study is a prospective, observational cohort study that enrolled patients switching EHLs or on standard replacement therapy after informed consent following local ethics approval and was registered at www.clinicaltrials.gov (NCT02938156). The study was paused during the COVID pandemic. Here the baseline results are presented for pain, activity and quality of life and their correlations. Pain evaluation was assessed through the brief pain inventory (BPI) 7-day recall, quality of life by EuroQol-5 Dimension (EQ5D5L) and physical activity through the international physical activity questionnaire (IPAQ). The BPI assess severity of pain and the interference with activities. IPAQ assess physical activity undertaken across a comprehensive set of domains. Three levels of physical activity are used to classify the populations: 'low', 'moderate', and ' high'. Result(s): A total of 231 HA and 97 HB were included in the analysis, of whom 231 had switched to EHL products and 96 were on standard replacement therapy. The levels of Physical Activity were similar between Haemophilia types, with approximately 46%, 32% and 22% of patients reporting high, moderate, and low physical activity, respectively. BPI mean (+/-SD) severity score in HA was 2.86 (+/-2.1), HB 3.24 (+/-2.0);interference score HA 3.22 (+/-2.8), HB 3.09 (+/-2.5), mean EQ5D5L visual analogue scale (VAS) for HA 72.92 (+/-15.5) and HB 71.10 (+/-18.2). Within instruments, IPAQ sub-scores and BPI average scores were highly correlated. Between instruments, the strongest linear correlations were seen between theVAS and the BPI scores (R=-0.59, p< 0.0001, n=206 for the average interference score, R=-0.57, p< 0.0001, n=208 for the average pain severity, v.s. the VAS). Correlations between the IPAQ total score and either VAS or BPI scores were weaker, even when limiting to patients with moderate or high activity and using a log scale given the skewed distribution of the IPAQ summary measure. Discussion/Conclusion: The study demonstrates for the first time a strong correlation between pain and quality of life, and weaker correlation between physical activity and quality of life.

Dynamic matching of oxygen uptake kinetics and muscle deoxygenation in post-COVID-19

Recent studies showed that post-COVID-19 patients with reduced pulmonary oxygen uptake (VO2p) kinetics, exhibited a lower peripheral oxygen extraction [lower C(a-v) O2 /Ca O2 ] rather than a central cardiac limitation (supernormal predicted exercisepeak cardiac output), opening further questions of what is impacting VO dynamics. We proposed to investigate the dynamic matching of VO2p , increase of heart rate (HR) and muscle deoxygenation (deoxy[Hb + Mb]) at the onset of heavy-exercise in post-COVID-19 patients. We expected to find a slowness of VO unrelated to circulatory impairment. 12 patients (90 days after onset of symptoms) were compared to 10 healthy controls. The VO rate of change, deoxy[Hb + Mb] in vastus lateralis (by near infrared spectroscopy) and HR were analyzed during a constant work-rate exercise test up to limit of tolerance (~70%peak work-rate). Post-COVID-19 patients had significantly slower VO2p kinetics than controls (Tau-VO2p 52+/-9 vs 40+/-11 seconds(s);p=0,001 and MRT-VO 70+/-12 vs 51+/-10 s;p<0,001). In contrast, t1/2 -HR was faster in patients (65+/-28 vs 85+/-20 s, p=0,04). Not only deoxy[Hb + Mb] dynamics were not accelerated compared to controls, suggesting normal muscle microvascular O2 delivery, but significantly slower (MRT-deoxy[Hb + Mb] 25+/-7 vs 20+/-2 s;p=0,02)(Figure 1). In conclusion, a sluggish on-exercise VO2p in these patients seems unrelated to central and peripheral circulatory adjustments. .

Infection with SARS-CoV-2 may alter the half-life of desmopressin (DDAVP) in children with central diabetes insipidus

Background: Central diabetes insipidus (CDI) is characterised by a central deficiency of arginine vasopressin (AVP) with polyuria and polydipsia. The etiology is heterogeneous. The treatment of choice is the oral or nasal application of DDAVP (synthetic analogue of AVP). CDI in the context of coronavirus disease 2019 (COVID19) has been reported in an individual case. Case Report: We present a 9-year old male with CDI of uncertain etiology. The reason for presentation was polydipsia (5 liters/ day) and polyuria/ nocturia. MRI showed a nodular thickening of the pituitary stalk and lack of T1w hyperintensity of the neurohypophysis. As expected, the level of CT-proAVP (copeptin) in serum was very low (< 2.7 pmol/litre) despite increased osmolality in serum of 306 mosm/kg. Sodium in serum was high with a maximum of 151 mmol/l. Laboratory analysis showed no involvement of other pituitary axis. Therapy was initiated with DDAVP at 1.2 mug in the morning and 0.6 mug in the evening (nasally). Treatment showed normalisation of polyuria, polydipsia, serum sodium levels and drinking quantity (2 liters/ day). The most recent dose was 6 mug in the morning and 1.8 mug in the evening. One year later the patient complained of sore throat. The pain was gone the following morning. A PCR test was positive for SARS-CoV-2. Surprisingly, with the onset of the sore throat, the half-life of the usual dosage of DDAVP therapy was significantly prolonged. Thus, the boy received the usual 1.8 mug of desmopressin in the evening (day of onset of symptoms). The effect lasted for 17 hours. Thus, the duration of action was prolonged by approximately 6 hours. The morning dose was skipped. The evening dose of 1.8 mug was then administered again at 1 p.m. at noon. This lasted for 18 hours. Thus, the duration of action was prolonged again by approximately 5 hours. After three days, the regular dosage and timing could be reintroduced. Furthermore, there was no adjustment of the dosage and no change of the manufacturer, pharmacy, application or storage of the preparation in the temporal context. Conclusion(s): In the context of a clinically mild infection with SARS-CoV-2, the half-life of DDAVP was significantly prolonged with the onset of clinical symptoms. Our case report is of clinical relevance, as even mild COVID19 may lead to a change in DDAVP pharmacokinetics. This knowledge may reduce the risk of dilutional hyponatremia.

Evaluation of Bivalirudin Anticoagulation in Patients on Ecmo Due to Covid-19 Respiratory Failure

INTRODUCTION: Patients supported on extracorporeal membrane oxygenation (ECMO) due to COVID-19 are at an increased risk of both thromboembolic complications and thrombocytopenia. Bivalirudin, a direct thrombin inhibitor, is increasingly being utilized for anticoagulation in the ECMO patient though there is largely a lack of literature within the COVID-19 population. The objective of our study was to evaluate the safety and efficacy of alternative anticoagulation with bivalirudin in patients on ECMO with COVID-19 respiratory failure. METHOD(S): This was a non-interventional retrospective chart review conducted at a single center large community hospital between January 2020 - November 2021. We included both venovenous (VV) and venoarterial (VA) adult ECMO patients anticoagulated with bivalirudin that tested positive for COVID-19. Patients were excluded if their duration of ECMO cannulation was less than 48 hours. Descriptive statistical analyses were performed utilizing median with interquartile range and frequency with percent as appropriate. RESULT(S): Overall, 180 ECMO patients were included in the study. The duration of ECMO cannulation was 29 (9-54) days and our cohort experienced a 42% mortality rate. The rate of thrombotic events including in-circuit thrombosis, arterial and venous thrombotic events was 22%. The median initial platelet count on ECMO was 206 (157-274) and the median nadir was 85 (48-121). ELSO defined major bleeding occurred at a rate of 53% within this cohort. CONCLUSION(S): To our knowledge, this study describes the largest number of patients anticoagulated with bivalirudin for ECMO secondary to COVID-19. Our results suggest similar rates of thrombotic events compared to ELSO registry data. While the half-life of bivalirudin is short, clinicians should still be cautious of bleeding due to lack of a specific reversal agent. Retrospective studies with a comparator cohort, as well as randomized trials are warranted to further evaluate the selection of intravenous anticoagulants in the ECMO population with and without COVID-19.

Higher Doses of Adintrevimab, an Extended Half-Life Monoclonal Antibody, for the Treatment and Prevention of COVID-19: Preliminary Results from a Phase 1 Single Ascending-Dose Study

Background. Adintrevimab is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential. Adintrevimab is being assessed in two separate phase 2/3 clinical trials: the EVADE trial for prevention of COVID-19 in both post-exposure and preexposure settings and the STAMP trial for treatment of COVID-19. Here we report higher doses being evaluated in a healthy volunteer study given that emerging variants may have varying susceptibilities to adintrevimab. Previous results 300 mg IM, 600 mg IM, and 500 mg IV cohorts have been reported. Methods. This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18-50 years with no current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 high dose cohorts (N=10/cohort: n=8 adintrevimab, n=2 PBO): adintrevimab 1200 mg IM, 1200 mg IV, and 4500 mg IV. Safety, tolerability, and pharmacokinetics (PK) were assessed up to 21 days post dose. Results. Overall, 30 participants received adintrevimab (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK for 1200 mg IV are reported. Through 21 days post dose all doses were well-tolerated, with no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions reported. The observed PK profile of the 1200 mg IV dose included Cmax of 423+/-105 mug/ml. Comparison of 500 mg and 1200 mg IV doses indicate dose proportionality of Cmax and exposure (AUC Day 21). Conclusion. A single dose of adintrevimab, up to 4500 mg, was well tolerated. These preliminary safety data and PK support potential use of higher doses of adintrevimab as needed to address emerging SARS-CoV-2 variants.

Antiviral Drugs for the Treatment of Covid-19 Patients: Applications of Drug Monitoring

In the last years, several studies on new and/or repurposing antiviral drugs were initiated to fight Coronavirus disease 2019 (COVID-19) pandemic. Three antivirals have so far been authorised in Italy for the treatment of COVID-19 in adults who do not need supplemental oxygen and who are at high risk of progressing to severe COVID-19. Specifically, the drugs currently authorized are Remdesivir (intravenous route) and the orally administered Molnupiravir and Nirmatrelvir-Ritonavir (Paxlovid). Remdesivir is a prodrug of the nucleotide analogue (GS-441524) which inhibits the SARS-CoV-2 RNA-dependent RNA polymerase. Remdesivir has been shown to improve the COVID-19 outcome in different settings. Molnupiravir is a prodrug that after entering in the cells changes into an active form of triphosphate, ready to be incorporated into viral genome causing many errors in SARS-CoV-2 RNA. In a clinical trial, Molnupiravir compared to placebo showed a 30% reduction of COVID-19-related hospitalizations. Paxlovid is a combination of Nirmatrelvir and Ritonavir. Nirmatrelvir acts by inhibiting protease enzyme, essential step to transform some viral proteins into their final functional form. The relative risk reduction of hospitalization or all-cause death at day 28 for Paxlovid compared to placebo was 88%. To guarantee safe and effectiveness of the pharmacological therapies, the evaluation of patient's pharmacokinetics (PK) profile is mandatory. Therefore, the monitoring of drug concentration of antivirals against SARS-CoV2 could be pivotal to optimise drug regimens, increase efficacy and avoid drug-related toxicity and to evaluate intra-individual variability and drug-drug interactions. Actually, few data on antiviral drugs concentrations in COVID-19 subjects are published. Among them, the most interesting are the following: i) Remdesivir and its main metabolite showed high PK interpatient variability due to both age and renal function in COVID-19 inpatients. The PK variability may have a potential effect in determining the efficacy of Remdesivir administration in patients affected by COVID-19. ii) Molnupiravir metabolite penetration into upper airways and mucosal secretions was demostred. These data could support the use of molnupiravir in a prophylaxis for SARS-CoV-2 infection iii) Nirmatrelvir displays a short half-life, which could result in suboptimal drug exposure and difficulties in achieving efficacy. Therefore, there is the need to use ritonavir (CYP3A4 Inhibitor) to slow down the metabolism and to increase the plasma concentrations of Nirmetrelvir. Drug-drug interactions are expected when drugs metabolized by CYP3A4 are co-administered with Paxlovid. Further research on antiviral drugs concentrations in COVID-19 patients could help to define therapeutic strategies more efficient and appropriate to treat SARSCoV-2 infection.

Pharmacokinetics of Remdesivir for Treatment of COVID-19 in a Child on Intermittent Hemodialysis

Introduction: Remdesivir is FDA approved for treatment (txt) of COVID19 in hospitalized adults and older children but is available only through an FDA EUA in pts <12 yo or <40 kg due to limited safety. Remdesivir is not recommended for use in pts with eGFR < 30 mL/min/1.73m2 due to renal excretion and limited data. Children with ESKD have increased morbidity and mortality secondary to COVID-19 and limited txt options. Determining pharmacokinetics (PK) of children on dialysis remains a priority. Here we report the PK of remdesivir and its active metabolite (GS-443902) for txt of COVID19 in a 2 yo on intermittent hemodialysis (IHD). Case Description: A 2 yo male with ESKD on chronic IHD was admitted in December 2021 after developing respiratory distress and hypoxia. SARS-COV-2 PCR was positive and chest x-ray showed viral airway disease. Due to severity of illness, he was treated with 2 doses of intravenous remdesivir (5 mg/kg loading dose after IHD #1 and 2.5 mg/kg after his next IHD 44 hours later.) The plasma concentration of remdesivir quickly decreased from 112 ng/mL to undetectable between 1-and 6-hours post-infusion. GS-441524 levels rose between 1-and 6-hours post-infusion (694 ng/mL to 837 ng/mL) and remained stable at 898 ng/mL 2 days later, prior to the next IHD (fig 1), consistent with minimal clearance between IHD. GS-441524 during IHD was calculated to have an elimination rate constant of 0.154 hr-1 with a half-life of 4.5 hours during iHD. HD performed prior to the second dose of remdesivir reduced GS-441524 plasma concentration by 37%. We did not observe accumulation of remdesivir, and GS-441524 accumulation was prevented by IHD. The pt was discharged after 4 days and did not have sequelae of txt with remdesivir. Discussion(s): We report successful and safe txt of a COVID positive IHD dependent toddler with remdesivir. Given limited options for txtt of COVID19 in this vulnerable population, additional exploration of remdesivir kinetics is needed to fully understand safety and efficacy.

Toxicokinetics of metformin overdose treated with CVVHDF

Background: Metformin is the most commonly used diabetes medication and at supratherapeutic levels can result in a severe type-A metabolic lactic acidosis known as metformin-associated lactic acidosis (MALA). Treatment of MALA includes aggressive fluid resuscitation, supporting blood pressure and correcting acidosis. Renal replacement therapy (RRT), usually hemodialysis (HD) is recommended in severe cases with refractory acidosis (with elevated lactate), altered mental status, or shock. To our knowledge, this is the second report of metformin half-life during treatment with continuous veno-venous hemodiafiltration (CVVHDF). Case report: A 53-year-old man died following a reported acute on chronic ingestion of 80 g of his metformin tablets resulting in severe, refractory shock and MALA. His peak serum metformin concentration was 53mcg/mL (therapeutic range 1-2mcg/mL), peak lactic acid concentration was 49.7 mmol/L, and arterial pH nadir was 7.06. Serial serum metformin concentrations were obtained while on RRT;both HD and CVVHDF. The switch from HD to CVVHDF was done due to staffing shortages during the COVID-19 pandemic. The patient died despite aggressive therapy with renal replacement therapy and multiple vasopressors on hospital day five. Serial metformin concentrations during CVVHDF suggested a half-life of 33-h. Discussion(s): Hemodialysis has been reported to clear metformin at a rate greater than 200mL/min and continuous venous-venous hemofiltration (CVVH) at greater than 50mL/min. In this case, metformin levels appear to follow first-order elimination kinetics during CVVHDF with an estimated half-life of 33 h. Comparatively, metformin has a half-life of 4.7-5.5 h during HD. To our knowledge, this is the second report of estimated metformin half-life while using the CVVHDF form of continuous renal replacement. The previous case report measured a half-life of 16.5 h on CVVHDF. This case report shows CVVHDF decreases half-life of metformin and provides first order elimination in the setting of overdose. Conclusion(s): The early initiation of HD appears warranted but prognostic indicators have not been well established. In the absence of HD availability, other forms of RRT (e.g., CCVHDF) can be used and may provide first-order elimination of metformin.

SUCCESSFUL USE OF BIVALIRUDIN DURING THE THIRD TRIMESTER OF PREGNANCY WHILE ON EXTRACORPOREAL MEMBRANE OXYGENATION

SESSION TITLE: Close Critical Care Calls SESSION TYPE: Case Reports PRESENTED ON: 10/18/2022 11:15 am - 12:15 pm INTRODUCTION: Heparin is the preferred anticoagulant for use in pregnancy while on extracorporeal membrane oxygenation (ECMO) (1). Alternatives to heparin in this patient population are not well studied as heparin-induced thrombocytopenia is rare in pregnancy. Parenteral non-heparin anticoagulants available in the United States include the direct thrombin inhibitors argatroban and bivalirudin, both of which are utilized in ECMO. Guidelines recommend avoidance of these agents in pregnancy if at all possible (2). Whereas case reports support the safe use of argatroban in pregnancy, to our knowledge, there are no known documented reports of bivalirudin use in this patient population (3). Here we describe the successful use of bivalirudin during pregnancy. CASE PRESENTATION: A 25 year old G2P1 was transferred to our institution at 28 weeks gestation for further management of acute hypoxic respiratory failure secondary to COVID-19. On hospital day 2 the patient was urgently placed on venovenous (VV) ECMO for refractory hypoxemia, high dead space with acidosis, and the inability to provide adequate gas exchange and lung protection with mechanical ventilation alone. Following ECMO cannulation with a 25f cannula in the right femoral vein and a 21f cannula in the right internal jugular vein, she was anticoagulated with heparin at a rate of 12 units/kg/hr. This was titrated to target a PTT goal of 60-80 seconds. On ECMO day 2, the TEG demonstrated a markedly hypocoagulable state, and the heparin nomogram called for increasing heparin dosing based on PTT. Given the already high dose of heparin that the patient was on (32.9 units/kg/hr), the decision was made to switch from heparin to bivalirudin to prevent over anticoagulation and reduce bleeding risk. Bivalirudin was titrated to a goal PTT of 50-60 seconds, with an initial rate of 0.15 mg/kg/hr (dose range 0.15-0.22 mg/kg/hr). Therapy was continued and on ECMO day 11, at 29w6d the patient delivered via cesarean section. Bivalirudin was discontinued 2.5 hours prior to the surgical procedure which resulted with no fetal bleeding complications. The patient was decannulated from ECMO on day 20 and was later discharged from the hospital. The newborn is developing well and meeting age adjusted milestones. DISCUSSION: Bivalirudin was selected based on institutional experience and the pharmacokinetic properties of the drug (half-life of 25 minutes) as we considered a situation where an emergent delivery may be indicated. Bivalirudin successfully prevented clotting of the circuit with no maternal or fetal bleeding complications during its use. CONCLUSIONS: Our case report describes a multidisciplinary approach to managing a pregnant patient on ECMO requiring anticoagulation using an alternative medication to heparin. This is the first documented use of bivalirudin in pregnancy. Reference #1: ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support Extracorporeal Life Support Organization, Version 1.4 August 2017. Ann Arbor, MI, USA www.elso.org. Reference #2: Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl): e691S–736S Reference #3: Young SK, Al-Mondhiry HA, Vaida SJ, et al. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy 2008;28: 1531–6. DISCLOSURES: No relevant relationships by Jacqueline Finger No relevant relationships by Caitlin Gluck No relevant relationships by Cameron Hypes No relevant relationships by John Rathbun

HEALTH PROFESSIONALS' PERSPECTIVES on the USE of JANUS KINASE INHIBITORS to TREAT PATIENTS with INFLAMMATORY ARTHRITIS

Background: Janus kinase inhibitors (JAKi) are relatively new to the feld of rheumatology and provide health professionals in rheumatology (HPRs) with more therapeutic options for treating infammatory arthritis (IA), specifcally rheumatoid arthritis (RA) and psoriatic arthritis (PsA) [1]. Aside from a different target, JAKi differ from often currently prescribed biologics by being administered orally. To date, there is a lack of evidence on what HPRs think about their real-world use and how the COVID-19 pandemic affects JAKi prescription. Objectives: To explore UK-based HPRs' perspectives towards JAKi use in IA patients, and in the context also of the COVID-19 pandemic. Methods: A 15-item anonymous online survey, with both closed and open-ended questions, was designed and piloted on 5 HPRs with amendments made based on their feedback. The survey was advertised on Twitter and shared by email in September 2021. Data were exported from the online survey platform and analysed descriptively with the assistance of statistical software. Results: Fifty-one HPRs responded to the survey: 37 Consultants, 7 Registrars, 5 Clinical Nurse Specialists, 1 Clinical Fellow and 1 'other rheumatology role' (not stated). Responses were received from 11/12 UK regions. Most represented was Greater London (18%) and North-West England (16%). 69% of respondents worked in secondary care, with the remaining 31% in tertiary care. The majority (40%) spent 1-25% of their job role doing research, followed by 27% who were not research active. 60% of HPRs indicated that 1-5% of their RA and/or PsA patients take a JAKi (no HPRs had more than 15% of their RA/PsA patients on a JAKi). 96% of HPRs indicated that they prescribe JAKi in their clinical practice, with 91% of those who prescribe following their local guidelines. 72% of respondents who prescribe JAKi, prescribed them 'frequently' as a monotherapy. Figure 1 shows responses chosen for when JAKi therapy is usually started and for feeling less confdent with JAKi prescription. Of those HPRs who prescribe, 17% have continued JAKi in their patients. When discontinuation occurred, the most common reasons chosen (multiple responses allowed) were 'due to inefficacy' (60%), 'due to other adverse events' i.e., non-major adverse cardiovascular events (32%) and 'due to herpes zoster infection' (28%). 55% of HPRs would consider switching patients to another JAKi after initial failure. Across prescrib-ers, 49% indicated no impact of the COVID-19 pandemic on their prescribing of JAKi. Common reasons chosen for a change in prescribing patterns for JAKi as a result of the pandemic (multiple responses allowed) included: prescribing them more as 'an alternative to infusions, in order to reduce hospital visits' (23%) and as 'an alternative to injections, in order to reduce at-home training visits' (21%). This was followed by 'other reason' (15%) with the free text from all 7 respondents highlighting the benefts of the shorter half-life of JAKi e.g., 'Prescribed more as quick on and quick off so can be discontinued quickly in event of severe infection' (Registrar, Greater London). Safety concerns around the use of JAKi were raised in 13/14 free text comments left at the end of the survey e.g., 'I am concerned about recent reports of increased VTE [venous thromboembolism] and malignancies' (Consultant, Yorkshire and the Humber) and 'Concerns about cardiovascular safety' (Clinical Fellow, Scotland). Conclusion: A large proportion of HPRs indicate confdence in prescribing JAKi to their patients with IA, adhering to local guidelines. JAKi are largely prescribed as monotherapy, with the most frequent reason for discontinuation being ineffi-cacy. The COVID-19 pandemic seems to have positively impacted JAKi prescription, however, safety concerns over JAKi use remain for some HPRs.

A Case of Beriberi After MIS-C

Introduction: As of June 2021, 4 million children have tested positive for COVID-19 in the US. In contrast to adults, children are often hospitalized with gastrointestinal symptoms including persistent vomiting. Pancreatitis has also been seen in MISC, which can lead to malnutrition. Most physician learn about thiamine deficiency and Wernicke Encephalopathy in patients with severe alcoholism or in low-income settings. We cared for a child with Wernicke Encephalopathy due to subacute malnutrition and weight loss after pancreatitis secondary to MISC in the US. Case Description: A 13-year-old female presented to Levine Children's Hospital with weight loss. She was diagnosed with COVID on 1/23/21 with 1 week of URI symptoms, with baseline weight 165 pounds (BMI 31.1). She was seen in an Emergency Department (ED) on 3/1/21 for vomiting with lipase 350u/L;she received fluids and was discharged. She represented on 3/7/21 with persistent symptoms weighing 135.5 pounds (BMI 25.6) with lipase 790u/L. She was discharged after three days with a diagnosis of post-COVID pancreatitis and lipase 600u/L. After discharge, she continued losing weight despite ondansetron. She followed up with GI on 3/15, weighing 130 pounds (BMI 24.5). An abdominal MRI and endoscopy were normal. She was started on omeprazole and cyproheptadine. She presented to Levine Children's Hospital on 3/24/21 for a second opinion. Upon admission, her serum lipase was 895u/L and she weighed 115 pounds (BMI 21.7). She was started on dextrose-containing fluids and developed seizures on 3/27/21. MRI brain was normal. Ophthalmology noted bilateral abducens nerve palsy. She developed worsening mental status and respiratory failure, so was intubated. A repeat MRI brain revealed posterior reversible encephalopathy syndrome and findings specific for Wernicke Encephalopathy. Thiamine level was low, and empiric thiamine was initiated. She was started on feeds and clinically improved. She was then extubated and showed improvements in her motor function and ability to follow commands. She transferred to inpatient rehab and continues to make progress. Discussion: Identification of the degree of malnutrition for this patient was difficult to obtain due to non-communicating EMRs. This limited the providers' ability to accurately quantify the degree of weight loss and the potential for Thiamine deficiency. The combination of limited body storage and short half-life can result in total depletion of thiamine stores within 2 weeks leading to altered mental status. Unfortunately, stigmatization of obesity in children has been well documented and malnutrition may be overlooked due to a normal BMI. Conclusion: Obtaining growth charts for patients presenting with weight loss is important as they provide objective data and help prevent obesity bias. If a child has a history of weight loss and develops altered mental status, vitamin B deficiencies should be considered in the differential. Pancreatitis associated with MIS-C can cause significant malnutrition leading to Wernicke Encephalopathy.