Days Of Infusion Research Articles

#2421 Kidney injury in scleroderma: serum level of fibroblast growth factor-23, klotho and neutrophil gelatinase-associated lipocalin after iloprost infusion

Abstract Background and Aims Systemic sclerosis (SSc) is characterized by progressive derangement of the microcirculation leading to a state of chronic tissue hypoxia with release of several inflammatory cytokines such as neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor-23 (FGF-23) and Klotho. Renal scleroderma associated-vasculopathy is characterized by vascular damage with normal renal function and increased intrarenal stiffness, assessed by renal resistive index (RRI) Aim of this study was to evaluate at baseline serum levels of FGF-23, Klotho and NGAL in SSc patients and healthy controls (HC) and to correlate the serum levels of these markers with microvascular damage of skin and kidney. Secondary aim was to evaluate the serum levels of FGF-23, Klotho and NGAL after Iloprost infusion. Method Twenty-one SSc patients and 20 HC were enrolled. All patients had a 2-months wash-out of Iloprost infusion before of clinical, laboratory and instrumental assessment. Peripheral venous blood was collected at three different time points for SSc patients: t0 immediately before the first Iloprost infusion (after 2-months wash-out period), t1 immediately after the first Iloprost infusion and t2 the day of the next Iloprost infusion (about 14 days from the last infusion). Results SSc patients had higher serum level of FGF-23 [18.7 pg/mL (± 6.4) vs 3.6 pg/mL (± 2.2), p < 0.001], Klotho [5.1 pg/mL (±0.8) vs 2.3 pg/mL (±0.6), p < 0.001] and NGAL [20.9 pg/mL (±2.6) vs 14.5 pg/mL (±1.7), p < 0.001] compared to HC. The one-way repeated-measures ANOVA showed that mean FGF-23 [F (2,40) = 71.255, p < 0.001], Klotho [F (1.405, 28.103) = 195.095, p < 0.001] and NGAL [F (2,40) = 48.024, p < 0.001] differed significantly between time points. Conclusion SSc patients had higher FGF-23, Klotho and NGAL than HC. Our present data demonstrate that microvascular damage is associated to chronic hypoperfusion with increased circulating markers such as FGF-23, Klotho and NGAL. For the first time, we demonstrated that Iloprost infusion reduces significantly serum level of FGF-23, Klotho and NGAL and it has showed to be a key role in renal vasculopathy in SSc patients. In literature, there are no data about the modification of these serum markers before and after vasoactive treatment, especially of Iloprost infusion.

Long peripheral catheters for intravenous infusions of iloprost or alprostadil therapy in rheumatologic outpatients.

Long peripheral catheters (LPCs) role in Difficult IntraVenous Access (DIVA) patients admitted to the emergency department has already been studied, resulting in a rapid, safe, and cost-effective procedure. Although their use in outpatient settings is established, there is a lack of studies assessing their benefits. In particular, rheumatologic outpatients affected by scleroderma, especially those affected by digital ulcers, are often treated with intravenous infusions of prostaglandin I2 (PGI2) analog (IV-PGI2A). From 1 October 2021 to 31 March 2024, we conducted a prospective study enrolling DIVA outpatients affected by systemic sclerosis or undifferentiated connective tissue disease who needed IV-PGI2A therapy at L. Sacco Hospital in Milan (Italy). Each treatment cycle consisted of four consecutive days of infusion of iloprost or alprostadil. The primary aim was to assess the efficacy and potential complications associated with LPCs for IV-PGI2A. Twenty-six patients were enrolled 23 were females (88.5%), and the median age was 72 years (IQR 56-78.7). In total, 97 LPCs were inserted, with a mean number of insertions per patient/year of 2.3. An increase in LPCs insertion during the 30 months of the enrollment period was observed. Eighteen patients required more than one LPC placement, and in 61% of them, the second venipuncture was executed at a different site. No procedural complications were registered (accidental puncture of the brachial artery, accidental median nerve puncture, bleeding) nor late complications (Catheter-Related Thrombosis, Catheter-Related Bloodstream Infections, Accidental Removal). Our experience shows that LPCs could be valuable and safe for rheumatologic outpatients. The increased number of insertions and new and total patients enrolled each year defines the satisfaction of patients and health care professionals.

Safety and efficacy of autologous adipose tissue-derived stem cell transplantation in aging-related low-grade inflammation patients: a single-group, open-label, phase I clinical trial

BackgroundInflamm-aging is associated with the rate of aging and is significantly related to diseases such as Alzheimer’s disease, Parkinson’s disease, atherosclerosis, heart disease, and age-related degenerative diseases such as type II diabetes and osteoporosis. This study aims to evaluate the safety and efficiency of autologous adipose tissue-derived mesenchymal stem cell (AD-MSC) transplantation in aging-related low-grade inflammation patients.MethodsThis study is a single-group, open-label, phase I clinical trial in which patients treated with 2 infusions (100 million cells i.v) of autologous AD-MSCs were initially evaluated in 12 inflamm-aging patients who concurrently had highly proinflammatory cytokines and 2 of the following 3 diseases: diabetes, dyslipidemia, and obesity. The treatment effects were evaluated based on plasma cytokines.ResultsDuring the study’s follow-up period, no adverse effects were observed in AD-MSC injection patients. Compared to baseline (D-44), the inflammatory cytokines IL-1α, IL-1β, IL-8, IL-6, and TNF-α were significantly reduced after 180 days (D180) of MSC infusion. IL-4/IL-10 at 90 days (D90) and IL-2/IL-10 at D180 increased, reversing the imbalance between proinflammatory and inflammatory ratios in the patients.ConclusionAD-MSCs represent a potential intervention to prevent age-related inflammation in patients.Trial registrationClinicalTrials.gov number is NCT05827757, first registered on 13th Oct 2020

Role of invasive hemodynamics monitoring in sepsis intensive care

The objective was to study the effect of early planned use of transpulmonary thermodilution (TPTD) and therapeutic measures to stabilize blood circulation on the clinical outcome of sepsis.Materials and methods. The cohort study involved 132 patients with abdominal sepsis with SOFA >7 and blood lactate >1.6 mmol/L. Septic shock was diagnosed in 56 % of patients. TPTD in the early periods of intensive care was began in 53.8 % of patients. Logistic regression and ROC-analysis were used to process the data.Results. Early use of invasive monitoring (OR 2,3715, 95 % CI 1,1107–5,0635, p=0,026, AUC 0.655) and infusion volume >43 ml/kg per day (OR 1.0313, 95 % CI 1.0073–1.0558, p=0.01, AUC 0.677) were predictors of survival in patients with abdominal sepsis. The use of TPTD compared to patients of group II was accompanied by an increase in the daily infusion volume (53.7 [38.1–63.5] vs 38.2 [29.9–47.2], ml/kg per day, p = 0.0001), more frequent use of inotropic drugs (39.4 vs 16.4 %, p = 0.004), and higher level of the inotropic scale (0 [0–4.7] vs 0 [0–0], p = 0.01). There were no differences in the frequency of prescription (57.7 vs 65.5 %, p = 0.376) and dosages (0.2 [0.1–0.4] vs 0.3 [0.2–0.4] μg/kg/min, p = 0.554) of norepinephrine. Twenty-eight-day mortality in groups I and II was 31 and 50.8 % (p = 0.022), hospital mortality was 32.9 and 54.0 % (p = 0.014).Conclusion. When assessed by SOFA > 7 points and lactatemia > 1.6 mmol/L, the onset of TPTD and infusion volume > 43 mL/kg/day increase the likelihood of survival of patients with abdominal sepsis, as a result, 28-day and hospital mortality decrease by 1.6 times. The use of invasive monitoring of central hemodynamics in this clinical situation is accompanied by an increase in the prescription of inotropes by 2.4 times with an unchanged intensity of norepinephrine use.

Verification of In Vitro Anticancer Activity and Bioactive Compounds in Cordyceps Militaris-Infused Sweet Potato Shochu Spirits.

Many liqueurs, including spirits infused with botanicals, are crafted not only for their taste and flavor but also for potential medicinal benefits. However, the scientific evidence supporting their medicinal effects remains limited. This study aims to verify in vitro anticancer activity and bioactive compounds in shochu spirits infused with Cordyceps militaris, a Chinese medicine. The results revealed that a bioactive fraction was eluted from the spirit extract with 40% ethanol. The infusion time impacted the inhibitory effect of the spirit extract on the proliferation of colon cancer-derived cell line HCT-116 cells, and a 21-day infusion showed the strongest inhibitory effect. Furthermore, the spirit extract was separated into four fractions, A-D, by high-performance liquid chromatography (HPLC), and Fractions B, C, and D, but not A, exerted the effects of proliferation inhibition and apoptotic induction of HCT-116 cells and HL-60 cells. Furthermore, Fractions B, C, and D were, respectively, identified as adenosine, cordycepin, and N6-(2-hydroxyethyl)-adenosine (HEA) by comprehensive chemical analyses, including proton nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy (FT-IR), and electrospray ionization mass spectrometry (ESI-MS). To better understand the bioactivity mechanisms of cordycepin and HEA, the agonist and antagonist tests of the A3 adenosine receptor (A3AR) were performed. Cell viability was suppressed by cordycepin, and HEA was restored by the A3AR antagonist MR1523, suggesting that cordycepin and HEA possibly acted as agonists to activate A3ARs to inhibit cell proliferation. Molecular docking simulations revealed that both adenosine and cordycepin bound to the same pocket site of A3ARs, while HEA exhibited a different binding pattern, supporting a possible explanation for the difference in their bioactivity. Taken together, the present study demonstrated that cordycepin and HEA were major bioactive ingredients in Cordyceps militaries-infused sweet potato shochu spirits, which contributed to the in vitro anticancer activity.

RNA aggregates harness the danger response for potent cancer immunotherapy

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Chronic central leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury

Kidney disease occurs in approximately 15% of the adult population, accounting for 37 million people in the US alone. Lack of blood flow is a major driver of kidney injury and no therapeutic modalities have shown substantial effcacy in treating ischemia-induced acute kidney injury (AKI). We recently demonstrated that activation of the brain leptin-melanocortin system dramatically improves cardiomyocyte mitochondrial function, energy metabolism and contractility, preserving cardiac function and preventing progression of heart failure following myocardial infarction and ischemia/reperfusion injury. In the present study we examined whether chronic intracerebroventricular (ICV) leptin administration protects the kidney against ischemia/reperfusion (I/R)-induced AKI. Twelve-week old male rats were implanted with an ICV cannula into the right lateral ventricle and 8-10 days after surgery, leptin (0.021 mg/hr, n=8) or saline vehicle (0.5 ml/h, n=8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On day 8 of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (i.e. 4th day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. Chronic leptin infusion reduced body weight by 20±1% compared to only 10±1% reduction in UIR-PF. UIR-Leptin rats also showed reduced right and left kidney weights (right: 1040±24 vs. 1281±36 and left: 1127±71 vs. 1707±45 mg, for UIR-Leptin and UIR-PF, respectively). Leptin infusion improved GFR (0.50±0.06 vs. 0.13±0.03 ml/min/g KW) and reduced kidney injury scores. Leptin treatment also increased circulating white blood cells count compared to UIR-PF rats (16.3±1.3 vs. 9.8±0.6 k/mL). Thus, leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and damage in a model of ischemia/reperfusion-induced AKI. NIH grants: (1R0DK1121411 (do Carmo), 1R0HL1630376 (da Silva/do Carmo), P20GM104357 (Hall), P30GM149404 (Hall) and U54GM115428 (Hall)). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Managing Infection Complications in the Setting of Chimeric Antigen Receptor T cell (CAR-T) Therapy.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has changed the paradigm of management of non-Hodgkin's lymphoma (NHL) and Multiple Myeloma. Infection complications have emerged as a concern that can arise in the setting of therapy and lead to morbidity and mortality. In this review, we classified infection complications into three categories, pre-infusion phase from the time pre- lymphodepletion (LD) up to day zero, early phase from day of infusion to day 30 post-infusion, and late phase after day 30 onwards. Infections arising in the pre-infusion phase are closely related to previous chemotherapy and bridging therapy. Infections arising in the early phase are more likely related to LD chemo and the expected brief period of grade 3-4 neutropenia. Infections arising in the late phase are particularly worrisome because they are associated with adverse risk features including prolonged neutropenia, dysregulation of humoral and adaptive immunity with lymphopenia, hypogammaglobinemia, and B cell aplasia. Bacterial, respiratory and other viral infections, protozoal and fungal infections can occur during this time . We recommend enhanced supportive care including prompt recognition and treatment of neutropenia with growth factor support, surveillance testing for specific viruses in the appropriate instance, management of hypogammaglobulinemia with repletion as appropriate and extended antimicrobial prophylaxis in those at higher risk (e.g.high dose steroid use and prolonged cytopenia). Finally, we recommend re-immunizing patients post CAR-T based on CDC and transplant guidelines.

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A.

Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation. Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec. To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4weeks after valoctocogene roxaparvovec infusion. Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals. Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.

Comparison of 2 Days versus 5 Days of Octreotide after Endoscopic Therapy in Preventing Early Esophageal Varices Rebleed: A Randomized Controlled Study

In esophageal varices bleeding, following the initial endoscopic hemostasis, it is recommended to administer vasoactive medications for a period of 2-5 days in order to avoid early rebleeding. Octreotide is the preferred vasoactive medication for treating variceal bleeding due to its favorable safety profile. This study aimed to assess the effectiveness of a 2-day octreotide infusion against a 5-day octreotide infusion following endoscopic intervention in avoiding early rebleeding of esophageal varices in individuals with cirrhosis. This study was a prospective, parallel, randomised controlled experiment conducted on a cohort of 184 subjects who were recruited from the endoscopy unit of the Tropical Medicine and Infectious Diseases Department at Tanta University Hospital in Egypt. The five days rate of rebleeding was 16.85% in the 2-days group against 15.91% in the 5- days group without significant difference (P= 0.865). In cirrhotic individuals with bleeding esophageal varices, a 2-day regimen of octreotide is equally efficacious as a 5-day regimen in avoiding rebleeding over a 5-day period, following successful control of bleeding with endoscopic intervention.

Use of Peripheral Nerve Stimulation and Perineural Catheter to Treat Phantom Limb Pain in a Multiple Limb Amputee: Case Report

BACKGROUND: Limb loss is a debilitating condition affecting many Americans and approximately 80% go on to suffer phantom limb pain (PLP). Peripheral nerve stimulation (PNS) and perineural catheter (PC) placement are promising treatment options for PLP. CASE REPORT: We present a 36-year-old man, who underwent right transhumeral and right transtibial amputations following a work-related accident. He developed significant PLP of both limbs. The right upper extremity PLP was treated first during the inpatient hospital course with a 5-day infusion of 0.5% ropivacaine via a PC. The right lower extremity PLP was later addressed in the outpatient setting with a diagnostic right sciatic/saphenous nerve block followed by a 60-day PNS lead placement, which provided > 50% pain relief from baseline. The patient continues to have > 50% pain relief in his RLE nearly 9 months after the initial procedure. CONCLUSIONS: Our case adds to a growing body of evidence that supports the utility of PNS and PC. Future studies should explore whether early intervention with PNS could improve long-term outcomes. In addition, clinicians could consider the use of a PC for intractable PLP as an opioid-sparing strategy in the inpatient setting where close monitoring is feasible. KEY WORDS: Phantom limb pain, traumatic amputation, peripheral nerve stimulation, perineural catheter

Brief Report: Clinical Outcomes by Infusion Timing of Immune Checkpoint Inhibitors in Patients With Locally Advanced NSCLC

IntroductionPrevious studies reported an association between immune checkpoint inhibitor infusion timing and the treatment effect in metastatic NSCLC. The present study assessed the association between durvalumab infusion timing and survival outcomes in patients with locally advanced NSCLC. MethodsPatients receiving durvalumab after chemoradiotherapy for locally advanced NSCLC at a single institution were retrospectively analyzed, and the association of the proportion of durvalumab infusions greater than or equal to 20% versus less than 20% after 3 PM with progression-free survival (PFS) and overall survival was assessed. ResultsA total of 82 patients were included, with a median age of 69 years (interquartile range, 62–74 years); of these, 67 patients (82%) were of male sex, and 78 patients (95%) had a history of smoking. The median number of durvalumab infusions per patient was 16 (interquartile range, 8–24). Patients with at least 20% of their durvalumab infusions after 3 PM (n = 12/82, 15%) had a significantly shorter PFS than those who did not (median: 7.4 mo versus not available [NA]; hazard ratio [HR], 2.43; 95% confidence interval [CI]: 1.11–5.34, p = 0.027), whereas overall survival was shorter among the former compared with the latter group (median: 22.4 versus NA; HR, 1.80; 95% CI: 0.73–4.42, p = 0.20). In addition, both backward stepwise multivariable analysis and propensity score–matching analysis revealed that receiving at least 20% of durvalumab infusions after 3 PM was significantly associated with worse PFS (HR, 2.54; 95% CI: 1.03–5.67, p = 0.047; and HR, 4.64; 95% CI: 1.95–11.04; p < 0.001, respectively). ConclusionsThe time of day of durvalumab infusions may impact survival outcomes in patients with locally advanced NSCLC.

Outcomes in Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy Recipients With Pre-Cellular Therapy SARS-CoV-2 Infection.

Hematopoietic cell transplant (HCT) or chimeric antigen receptor (CAR) T-cell therapy recipients have high morbidity from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are limited data on outcomes from SARS-CoV-2 infection shortly before cellular therapy and uncertainty whether to delay therapy. We conducted a retrospective cohort study of patients with SARS-CoV-2 infection within 90 days before HCT or CAR-T-cell therapy between January 2020 and November 2022. We characterized the kinetics of SARS-CoV-2 detection, clinical outcomes following cellular therapy, and impact on delays in cellular therapy. We identified 37 patients (n = 15 allogeneic HCT, n = 11 autologous HCT, n = 11 CAR-T-cell therapy) with SARS-CoV-2 infections within 90 days of cellular therapy. Most infections (73%) occurred between March and November 2022, when Omicron strains were prevalent. Most patients had asymptomatic (27%) or mild (68%) coronavirus disease 2019 (COVID-19). SARS-CoV-2 positivity lasted a median of 20.0 days (interquartile range, 12.5-26.25 days). The median time from first positive SARS-CoV-2 test to cellular therapy was 45 days (interquartile range, 37.75-70 days); 1 patient tested positive on the day of infusion. After cellular therapy, no patients had recrudescent SARS-CoV-2 infection or COVID-19-related complications. Cellular therapy delays related to SARS-CoV-2 infection occurred in 70% of patients for a median of 37 days. Delays were more common after allogeneic (73%) and autologous (91%) HCT compared to CAR-T-cell therapy (45%). Patients with asymptomatic or mild COVID-19 may not require prolonged delays in cellular therapy in the context of contemporary circulating variants and availability of antiviral therapies.

Gestational choline supplementation ameliorates T-maze reversal learning deficits induced by first trimester binge alcohol exposure in weanling lambs

In rodent models of fetal alcohol spectrum disorders (FASD), cognitive deficits are implicated in impaired T-maze spatial reversal learning. Rat studies have indicated supplemental administration of choline during the developmental period of alcohol exposure can ameliorate spatial reversal deficits. This study tested whether beneficial effects of prenatal choline supplementation could be confirmed in a sheep model of binge exposure in the first trimester equivalent. Two hypotheses were tested: 1) alcohol exposure would produce deficits in reversal of a T-maze position discrimination; and 2) gestational dietary supplementation of choline would ameliorate those deficits. Mated ewes were assigned to one of seven groups—a normal control (NC) group or one of six infusion treatment groups: saline control (SC; isotonic saline), saline control plus choline (SC-CH; isotonic saline plus choline, 10 mg/kg administered orally throughout each day of gestation), binge alcohol (BA; 1.75 g/kg alcohol per infusion day), binge alcohol plus choline (BA-CH; 1.75 g/kg/day alcohol plus choline), heavy binge alcohol (HBA; 2.5 g/kg/day alcohol), or heavy binge alcohol plus choline (HBA-CH; 2.5 g/kg/day alcohol plus choline). The alcohol infusions modeled a weekend binge drinking pattern over the first trimester-equivalent (gestational day 4-41). T-maze training began at 12 weeks of age, with daily sessions occurring 5 days/week. Lambs were given five days of habituation training, followed by five days of position discrimination training (3 trials per daily session, intertrial interval of 3 hours, reinforced side randomly assigned across subjects). Lambs were then given 10 days of training on the reversal task. There was no difference among groups during acquisition. Alcohol impaired reversal learning, and choline supplementation mitigated these deficits in the HBA-CH group. These results suggest that maternal dietary choline supplementation can ameliorate or prevent some impairments of executive function in a sheep model of FASD.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the US National COVID Cohort Collaborative (N3C).

The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented healthcare crisis, one that threatened to overwhelm health systems and prompted an urgent need for early treatment options for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. Randomised clinical trials established the safety and efficacy of monoclonal antibodies (mAbs) early in the pandemic; in vitro data subsequently led to use of the mAbs being discontinued, without clear evidence on how these data were linked to outcomes. In this study, we describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 treated with sotrovimab versus untreated patients. Electronic health records from the National COVID Cohort Collaborative (N3C) were used to identify US patients (aged ≥ 12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (27 September 2021-30 April 2022) who met Emergency Use Authorization (EUA) high-risk criteria. Patients receiving the mAb sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort, with the day of infusion as the index date. Untreated patients (no evidence of early mAb treatment, prophylactic mAb or oral antiviral treatment) were assigned to the untreated cohort, with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion in the sotrovimab cohort. The primary endpoint was hospitalisation or death (both all-cause) within 29 days of index, reported as descriptive rate and adjusted [via inverse probability of treatment weighting (IPTW)] odds ratio (OR) and 95% confidence interval (CI). Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis period, 4992 met the criteria for the sotrovimab cohort, and 541,325 were included in the untreated cohort. Before weighting, significant differences were noted between the cohorts; for example, patients in the sotrovimab cohort were older (60 years versus 54 years), were more likely to be white (85% versus 75%) and met more EUA criteria (mean 3.1 versus 2.2) versus the untreated cohort. The proportions of patients with 29-day hospitalisation or death were 3.5% (176/4992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts, respectively (unadjusted OR: 0.78; 95% CI: 0.67, 0.91; p = 0.001). In adjusted analysis, sotrovimab was associated with a 25% reduction in the odds of hospitalisation or death compared with the untreated cohort (IPTW-adjusted OR: 0.75; 95% CI: 0.61, 0.92; p = 0.005). Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalisation, mortality) in the period 27 September 2021-30 April 2022, which included Delta and Omicron BA.1 variants and an early surge of Omicron BA.2 variant.

The characteristics and impact on prognosis of cytopenia after anti-BCMA-CAR-T therapy in patients with relapsed and refractory multiple myeloma

Objective: To investigate the characteristics of cytopenia and its impact on prognosis in patients with relapsed and refractory multiple myeloma (RRMM) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) immunotherapy therapy. Methods: Clinical data of 36 RRMM patients received BCMA CAR-T therapy at the First Affiliated Hospital of Nanjing Medical University from April 2017 to March 2023 were retrospectively collected. Among them, there were 17 males and 19 females, with an age [M (Q1, Q3)] of 62 (53, 67) years. The follow-up deadline was August 31, 2023, and the follow-up time [M (Q1, Q3)] was 33 (10, 30) months. The characteristics of cytopenia at different time points before lymphodepleting chemotherapy and after CAR-T cell infusion in all patients were analyzed. Kaplan-Meier method was used to compare the differences in progression-free survival (PFS) and overall survival (OS) in patients with different clinical characteristics. Single-cell sequencing analysis was used to analyze the changes in hematopoietic stem cells in three patients after CAR-T cell therapy. Results: The incidence of cytopenia after BCMA CAR-T cell therapy in 36 RRMM patients reached 100%. The incidence of neutropenia peaked on the 7th and 28th day after cell infusion with a biphasic pattern of change.Patients with all grade neutropenia reached 61.1% (22/36) and grade 3 or higher reached 33.3% (12/36) on the 7th day, while patients with all grade neutropenia reached 67.9% (19/28) and grade 3 or higher reached 28.6% (8/28) on the 28th day (P<0.001),respectively. The occurrence rate of lymphopenia reached a peak on the day of CAR-T cell infusion [97.2% (35/36) patients showed lymphopenia, while 80.6% (29/36) patients showed grade 3 or higher lymphopenia] (P<0.001).The incidence of all grade of thrombocytopenia and severe thrombocytopenia (grade 3 or higher) peaked on the 14th day after cell infusion, with the rates of 69.4% (25/36) and 30.6% (11/36) respectively, which had a prolonged duration(P<0.001). Even after 12 months, 40% (8/20) of patients still experienced thrombocytopenia.The incidence of anemia peaked on the 7th and 14th day after cell infusion, with a rate of 100% (36/36) (P<0.001). 50% (10/20) of patients still had anemia even 12 months after cell infusion. Kaplan-Meier survival analysis showed that patients with thrombocytopenia < grade 3 had undefined OS, while patients with thrombocytopenia ≥grade 3 had shorter OS [17 (95%CI: 2-32) months, χ2=4.154, P=0.042], indicating a poorer prognosis. However, there was no statistically significant difference in the relationship between other cytopenia and survival (all P>0.05). Single-cell sequencing analysis of bone marrow cells revealed decreased proliferation, increased apoptosis, and cell cycle arrest of hematopoietic stem cells after CAR-T cell infusion. Conclusions: All patients experienced varying degrees of cytopenia after receiving BCMA CAR-T cell infusion, and patients with thrombocytopenia ≥grade 3 had shorter OS and poorer prognosis.

A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2–4 years, 70% for 5–9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.

P162 The Biosimilar Switch: IBD nurse's experience in Our Lady of Lourdes Hospital

Abstract Background A biological medication contains an active substance that is produced from a biological source such as living cells, hormones or enzymes. The active substance in a biological medicine is what makes the medicine work. Biological medicines are also called biologics. A biosimilar medicine is a biological medicine that is developed to be highly similar to an existing biologic but they are not identical and so cannot be considered to be generics. Biosimilars were introduced in Ireland in 2014. In 2018, Our Lady of Lourdes Hospital commenced a procurement programme to decide which Infliximab biosimilar to switch our patients to. This process would allow for a huge cost-saving to the hospital budget and also allowed for the allocation of a whole-time clinical nurse specialist to add the IBD nursing team. The infliximab biological switch was then carried out starting in October 2019. All patients received a letter explaining the switch and a booklet to explain the meaning of biosimilars. The patients were then either phoned or spoken to in person by either the IBD nurse or a GI pharmacist, and any questions or concerns addressed. Methods A patient satisfaction survey was sent to each patient 6 months after the switch. Each questionnaire was sent with a prepaid return envelope. The questionnaire consisted of 7 questions with tick box answers. 1. Gender? 2. Age? 3. Did you receive a letter and information booklet in the post prior to the day of your infusion switch. 4. Did you get the opportunity to talk to someone on the phone prior to your infusion? 5. Did you get the opportunity to speak to a nurse or pharmacist on the day of your infusion? If so who? 6. Were you given a named person to contact if you had any issues after our first infusion? 7. Were you happy with the overall experience of the infliximab biosimilar switch? Results 86 patients were switched from the originator to the biosimilar Flixabi. 22 responses were received. 1. 11 male; 11 female 2. Age 16-19 - 2; 20-29 - 1; 30-39 - 4; 40-49 - 4; 50-59 - 9; 70-79 - 1; preferred not to answer - 1. 3. 20 received the letter and booklet; 2 did not. 4. 15 spoke to someone on the phone; 6 did not and 1 could not remember. 5. 22 - spoke to a nurse; 0 - pharmacist. 6. 20 - yes; 2 - no. 7. 21 - yes; 1 - unsure. Conclusion Of the 86 patients who were switched 22 responded to the questionnaire. 21 patients were happy with their overall experience with how the switch was conducted.

Comparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals.

Metabolic measures are frequently used to predict type 1 diabetes (T1D) and to understand effects of disease-modifying therapies. Compare metabolic endpoints for their ability to detect preventive treatment effects and predict T1D. Six-month changes in metabolic endpoints were assessed for (1) detecting treatment effects by comparing placebo and treatment arms from the randomized controlled teplizumab prevention trial, a multicenter clinical trial investigating 14-day intravenous teplizumab infusion and (2) predicting T1D in the TrialNet Pathway to Prevention natural history study. For each metabolic measure, t-Values from t tests for detecting a treatment effect were compared with chi-square values from proportional hazards regression for predicting T1D. Participants in the teplizumab prevention trial and participants in the Pathway to Prevention study selected with the same inclusion criteria used for the teplizumab trial were studied. Six-month changes in glucose-based endpoints predicted diabetes better than C-peptide-based endpoints, yet the latter were better at detecting a teplizumab effect. Combined measures of glucose and C-peptide were more balanced than measures of glucose alone or C-peptide alone for predicting diabetes and detecting a teplizumab effect. The capacity of a metabolic endpoint to detect a treatment effect does not necessarily correspond to its accuracy for predicting T1D. However, combined glucose and C-peptide endpoints appear to be effective for both predicting diabetes and detecting a response to immunotherapy. These findings suggest that combined glucose and C-peptide endpoints should be incorporated into the design of future T1D prevention trials.

Outcomes for central venous catheter repair in patients receiving long-term home parenteral support: A descriptive cohort study.

Central venous catheter (CVC) complications are frequently reported in patients receiving home parenteral support (HPS). Compromised CVC integrity or breakage is one such issue. Repairing such breakages can potentially avoid costly and risky catheter replacements. We completed a retrospective descriptive cohort study using a prospectively maintained data set, in a national UK intestinal failure reference center. Repair success, CVC longevity, and catheter-related bloodstream infection (CRBSI) rates after repair were the primary outcome measures. A total of 763 patients received HPS. There were 137 CVC repairs: 115 (84%) tunneled CVCs and 22 peripherally inserted central catheters (PICCs) attempted in 72 patients. Of the 137 attempts at CVC repair, 120 (88%) were deemed to be successful, allowing a median duration of subsequent CVC use of 336 days following repair (range 3-1696 days), which equates to 99,602 catheter days of HPS infusion. Three patients had a CRBSI within 90 days of repair, and patients required admission to the hospital for refeeding on 14 occasions following repair, such that hospitalization was avoided in 103/120 (86%) occasions following successful CVC repair. There was no increase in the recorded rate of CRBSIs in patients undergoing CVC repair compared with the CRBSI rates of all HPS-dependent patients under our care during the study period (0.03 vs 0.344/1000 catheter days, respectively). This is the largest single-center experience to demonstrate that CVCs, including PICCs, used for the administration of HPS can be safely repaired, prolonging CVC longevity without leading to an increased risk of CRBSI.