Successive Doses Research Articles

Endovesical instillation of Cidofovir in the treatment of BK polyomavirus hemorrhagic cystitis after allogeneic hematopoietic cell transplantation

BackgroundHemorrhagic cystitis (HC) with BK polyomavirus (BKPyV) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT) that may lead to severe discomfort for the patient and significant morbidity (urinary obstruction, increased transfusion requirements and prolonged hospitalization). So far, there is no clear consensus on how to manage this complication. Patients and methodsHere, we report a single-center case series of 9 patients (4 children and 5 adults) treated with cidofovir endovesical (EV) instillation(s) for BKPyV-HC after alloHCT. EV Cidofovir was administered at a dose of 5 mg/kg, for 1 to 3 instillations (with a minimum delay between 2 successive doses of 5 days). ResultsEight out of the 9 treated patients with EV Cidofovir achieved a complete resolution of HC after 1–3 instillation(s), without recurrence of symptomatic infection within the next 3 months. Only 1 adult patient did not improve after treatment and developed severe morbidity (emphysematous cystitis). ConclusionAlthough this single-center case series of EV cidofovir for BKPyV HC after alloHCT shows encouraging results, only large prospective studies will definitively establish the effectiveness of this therapy.

Conditional probability and ratio-based approaches for mapping the coverage of multi-dose vaccines.

Many vaccines are often administered in multiple doses to boost their effectiveness. In the case of childhood vaccines, the coverage maps of the doses and the differences between these often constitute an evidence base to guide investments in improving access to vaccination services and health system performance in low and middle-income countries. A major problem often encountered when mapping the coverage of multi-dose vaccines is the need to ensure that the coverage maps decrease monotonically with successive doses. That is, for doses and , , where is the coverage of dose at spatial location . Here, we explore conditional probability (CP) and ratio-based (RB) approaches for mapping , embedded within a binomial geostatistical modeling framework, to address this problem. The fully Bayesian model is implemented using the INLA and SPDE approaches. Using a simulation study, we find that both approaches perform comparably for out-of-sample estimation under varying point-level sample size distributions. We apply the methodology to map the coverage of the three doses of diphtheria-tetanus-pertussis vaccine using data from the 2018 Nigeria Demographic and Health Survey. The coverage maps produced using both approaches are almost indistinguishable, although the CP approach yielded more precise estimates on average in this application. We also provide estimates of zero-dose children and the dropout rates between the doses. The methodology is straightforward to implement and can be applied to other vaccines and geographical contexts.

Low-Dose Hemibody Radiation, a Treatment Option for Recurrent Prostate Cancer: A Phase 2 Single-Arm Trial

PurposeNontargeted low-dose ionizing radiation has been proposed as a cancer therapeutic for several decades; however, questions remain about the duration of hematological changes and optimal dosing regimen. Early studies delivering fractionated low doses of radiation to patients with cancer used varying doses and schedules, which make it difficult to standardize a successful dose and scheduling system for widespread use. The aim of this phase 2 two-stage trial was to determine whether low-dose radiation therapy (LD-RT) reduced prostate-specific antigen (PSA) in patients with recurrent prostate cancer in efforts to delay initiation of conventional therapies that are known to decrease quality of life. The primary study outcome was reduction in PSA levels by at least 50%. Methods and MaterialsSixteen patients with recurrent prostate cancer were recruited and received 2 doses of 150 mGy of nontargeted radiation per week, for 5 consecutive weeks, with 15 participants completing the study. ResultsA maximal response of 40.5% decrease in PSA at 3 months was observed. A total of 8 participants remained off any additional interventions, of whom 3 had minor fluctuations in PSA for at least 1 year after treatment. The most common adverse event reported was mild fatigue during active treatment (n = 4), which did not persist in the follow-up period. No participants withdrew due to safety concerns or hematological abnormalities (ie, platelet ≤50 × 109/L, leukocyte ≤3 × 109/L, granulocyte ≤2 × 109/L). ConclusionsOur study did not meet the primary objective; however, LD-RT may be a potential therapy for some patients with recurrent prostate cancer by stalling rising PSA. This study also demonstrates that low-dose radiation is well tolerated by participants with minimal toxicities and no change in quality of life.

Nasopharyngeal DLBCL Misdiagnosed as a Nasal Polyp in an 84-Year-Old Patient: A Case Report

Malignant lymphoma is a malignant tumor that occurs in the lymphocytes but can also occur anywhere in the body. On the other hand, malignant lymphomas originating from the nasopharyngeal space are very rare. We experienced a case of 84-year-old female patient with a huge nasopharyngeal mass, who had no complaints other than right nasal congestion, intermittent rhinorrhea, and sneezing. A physical examination revealed a large, polypoid, transparent mass at her right nasal cavity. Nasal polyp was suspected and endoscopic sinus surgery was performed. On histological examination, she was diagnosed with diffuse large B cell lymphoma, with CD20, BCL-2, and BCL-6 positive. Low dose maintenance chemotherapy was carried out in consideration of the patient’s age. A complete remission is expected based on the imaging tests following chemotherapy. We report a huge malignant lymphoma that occurred in an elderly patient’s nasopharyngeal space and successful low dose chemotherapy with a review of literature.

Physical, Chemical, and Biological Properties of Chitosan-Coated Alginate Microparticles Loaded with Porcine Interleukin-1β: A Potential Protein Adjuvant Delivery System.

We previously developed chicken interleukin-1β (IL-1β) mutants as single-dose adjuvants that induce protective immunity when co-administered with an avian vaccine. However, livestock such as pigs may require a vaccine adjuvant delivery system that provides long-lasting protection to reduce the need for successive booster doses. Therefore, we developed chitosan-coated alginate microparticles as a carrier for bovine serum albumin (BSA) or porcine IL-1β (pIL-1β) and assessed their physical, chemical, and biological properties. Electrospraying of the BSA-loaded alginate microparticles (BSA/ALG MPs) resulted in an encapsulation efficiency of 50%, and those MPs were then coated with chitosan (BSA/ALG/CHI MPs). Optical and scanning electron microscopy, zeta potential analysis, and Fourier transform infrared spectroscopy were used to characterize these MPs. The BSA encapsulation parameters were applied to ALG/CHI MPs loaded with pIL-1β, which were not cytotoxic to porcine fibroblasts but had enhanced bio-activity over unencapsulated pIL-1β. The chitosan layer of the BSA/ALG/CHI MPs prevented burst release and facilitated sustained release of pIL-1β for at least 28 days. In conclusion, BSA/ALG/CHI MPs prepared as a carrier for pIL-1β may be used as an adjuvant for the formulation of pig vaccines.

Use of Calcitonin for Hypercalcemia in a Premature Neonate With Congenital Mesoblastic Nephroma.

We report on a premature neonate (31 4/7 weeks' gestation) who presented with hypercalcemia secondary to congenital mesoblastic nephroma (CMN), the most common type of renal tumor in neonates. Typical presentation includes a palpable abdominal mass or swelling and may include abdominal pain, hematuria, fever, or hypertension. A less common complication of CMN is hypercalcemia of malignancy. Although the primary management strategy for hypercalcemia of malignancy is to treat the underlying disease, there are several agents that can be used as well for acute hypercalcemia including fluids, loop diuretics, corticosteroids, bisphosphonates, and calcitonin. However, there is minimal evidence to guide efficacious and safe treatment selection and dosing as hypercalcemia is a rare complication of this tumor type. This case adds to the current body of literature as only the second case of parathyroid hormone-related peptide-mediated hypercalcemia in a preterm neonate treated with calcitonin and is the first to specify a successful dose escalation strategy of calcitonin for this indication.

EGR1 Haploinsufficiency Confers a Fitness Advantage to Hematopoietic Stem Cells Following Chemotherapy

Therapy-related myeloid neoplasms (t-MNs) share many clinical and molecular characteristics with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation, likely because of advanced age or chemotherapy-induced senescence. Here, we examined the effect of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs. In mice, under the exogenous stress of either serial transplant or successive doses of the alkylating agent N-ethyl-nitrosourea (ENU), Egr1-haploinsufficient hematopoietic stem cells (HSCs) exhibit a clonal advantage. Complete loss of EGR1 function is incompatible with transformation; mutations of EGR1 are rare and are not observed in the remaining allele in del(5q) patients, and complete knockout of Egr1 in mice leads to HSC exhaustion. Using chromatin immunoprecipitation sequencing (ChIP-seq), we identified EGR1 binding sites in human CD34+ cord blood-derived stem and progenitor cells (HSPCs) and found that EGR1 binds genes critical for stem cell differentiation, inflammatory signaling, and the DNA damage response. Notably, in the chromosome 5 sequences frequently deleted in patients, there is a significant enrichment of innate and inflammatory genes, which may confer a fitness advantage in an inflammatory environment. Short hairpin RNA (shRNA)-mediated silencing of EGR1 biases HSPCs toward a self-renewal transcriptional signature. In the absence of EGR1, HSPCs are characterized by upregulated MYC-driven proliferative signals, downregulated CDKN1A (p21), disrupted DNA damage response, and downregulated inflammation-adaptations anticipated to confer a relative fitness advantage for stem cells especially in an environment of chronic inflammation.

Effects of the size of the test dose on the SAR protocol for quartz optically stimulated luminescence dating of loess in the eastern Tibetan Plateau

Dating of quartz by optically stimulated luminescence (OSL) has been revolutionized with introduction of the test dose (TD) in development of a measurement sequence known as the single-aliquot regenerative-dose (SAR), whereby a valid sensitivity correction for the luminescence signal is provided in the measurement cycle. However, the size of the TD used in the SAR protocol remains controversial. Previous studies show that the TD has little effect on the equivalent dose (D e ) for young samples in luminescence dating in which the applicability of different deposits varies greatly in different regions. However, detailed studies are lacking on how TD size affects SAR–OSL results of samples with a relatively high D e range. In this study, typical loess samples with high D e values (∼60 Gy–∼250 Gy) from the eastern Tibetan Plateau were selected to investigate the effects of variation in TD size on the quartz SAR–OSL protocol. Dose recovery tests show that a known dose could be recovered successfully by applying different TDs. Test dose size has an effect on shapes of regenerated dose–response curves (DRCs) and has different influences on D e s and characteristic saturation doses for quartz samples with a high dose range. A TD size of 20%–30% D e is a good compromise for Tibetan loess with D e of ∼60–120 Gy in the quartz SAR protocol, and a TD size larger than 30% should be considered for samples with a larger D e . The results of this study highlight the importance of TD size in the SAR–OSL protocol for quartz samples with a high dose range. • Test dose size effect on the quartz SAR for high dose range is investigated. • Successful dose recovery test can be obtained by applying different test doses. • Test dose size has different influences on D e s and D 0 s. • A 20%–30% test dose size is a good compromise for D e of ∼60–120 Gy.

Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.

At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers. Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n=30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n=30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n=30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time. Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR=17.1-45.6); 12.5 mg/L (IQR=1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR=67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period. This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time.

A phantom-based study and clinical implementation of brainlab’s treatment planning system for radiosurgical treatments of arteriovenous malformations

Purpose. Development of a simple, phantom-based methodology allowing for pilot applications for the Elements TPS cranio-vascular module and clinical implementation prior to AVM treatments. Methods. A customized phantom was developed to be visible in MRI and CT images. High resolution digital subtraction angiograms (DSAs) and CT images of the phantom were acquired and imported into the Brainlab Elements treatment planning system. A clinical treatment plan with 5 arcs was generated in cranial vascular planning module and delivered to the phantom using a Varian TrueBeam STx Linac equipped with HD-MLCs and Brainlab ExacTrac imaging system for non-coplanar setup verification. The delivered dose was verified using a calibrated ionization chamber placed in the phantom. Upon verification of the TPS workflow, three patients with AVM who have been treated to date at our center using the Brainlab’s cranial vascular module for AVM are presented here for retrospective review. Results. The difference between the planed and measured dose by the ionization chamber was found to be less than 1%. Following a successful dose verification study, a clinical workflow was created. Currently, three AVM patients have been treated successfully. Clinical aspects of imaging and treatment planning consideration are presented in retrospective setting. Conclusions. Dose verification of the Brainlab Elements cranial vascular planning module for intracranial SRS treatments of AVM on Varian TrueBeam was successfully implemented using a custom-made phantom with <1% discrepancy. The Brainlab Elements’ cranial vascular module was successfully implemented in clinical workflow to treat patients with AVM. This manuscript provides a guideline for clinical implementation of frameless Linac-based AVM treatment using the Brainlab Elements TPS.

Successful dose escalation of lenvatinib for thyroid cancer after disease progression.

Lenvatinib is started at a standard dose, continuing with dose reduction and interruption, balancing between efficacy and adverse events (AEs). Because few drugs are available for thyroid cancer, efforts for continuing treatment with one agent, such as "dose escalation (DE)", are made. The dose is increased, aiming to regain the anti-tumor effect after dose reduction. The effects of lenvatinib DE in differentiated thyroid carcinoma (DTC) patients are reported. The efficacy of lenvatinib DE in DTC patients using the serum thyroglobulin (Tg) level and management of AEs was investigated. A total of 70 DE episodes in 33 patients were investigated. The median increased dose was 2.0 (1.0-14.0) mg, increased from 8.6 (2-16) mg to 10.1 (6-24) mg. The serum Tg level decreased in 53 DE episodes. Though the serum Tg level in 17 DE episodes was not decreased, the Tg rate of increase was decreased in 7 of these DE episodes using the Tg-doubling rate. Overall, clinical benefit was seen in 60 (86%) DE episodes. AEs that could not be controlled after DEs were seen in only 16% of cases. No intolerable AEs were observed in patients who received more drug holidays at the time of DEs compared to two times before the DEs. DE may become one of the standard treatment strategies after disease progression if AEs are well managed. Drug holidays may be a key for successfully controlling AEs with DE. DE can be useful for controlling progressive disease with increasing Tg levels.

Abstract 5424: Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN

Abstract Xevinapant, an antagonist of Inhibitor of Apoptosis Proteins (IAPs) showed significant improvement in locoregional control at 18 months (LRC18; primary endpoint), overall survival (OS) and progression-free survival (PFS) at an oral dose of 200 mg/day given on days 1-14 every 3 weeks in combination with CRT versus CRT with placebo in a phase II trial in patients with high-risk LA SCCHN (NCT02022098). In the dose escalation (DE) part of NCT02022098, 200 mg/day was the maximum tolerated dose and a trend of dose-response for efficacy in the 100-300 mg/day dose range was observed. The phase III TrilynX study of xevinapant plus CRT in patients with LA SCCHN is currently enrolling (NCT04459715). Here we present the integrated rationale for the recommended phase III dose (RP3D) of xevinapant 200 mg/day based on all available clinical and preclinical data and modeling and simulation (M&amp;S). At the RP3D, ~95% of the patients are projected to have free trough concentrations above in vitro IC50 for cIAP1 degradation (a pharmacodynamic [PD] marker), based on a population (pop) PK M&amp;S. In patients, average free concentration over the dosing interval at RP3D is similar to that associated with maximal efficacy in preclinical SCCHN models. Pop PK/PD M&amp;S suggests that maximal cIAP1 degradation is maintained in PBMCs with 100-200 mg/day doses during the 14-day dosing period, with a trend of dose-response for the partial cIAP1 degradation at the end of the 3-week cycle. Exposure response (E-R) analyses were conducted based on the pooled datasets of DE and randomized parts of study NCT02022098 (n=62 treated with xevinapant). Logistic regressions showed that probabilities of LRC18, overall response, complete response, and the composite safety endpoint of “mucositis and/or dysphagia” increase with increasing exposure (p&amp;lt;0.05). Statistically significant E-R relationships were not discernible for any other evaluated safety endpoints or for PFS, OS, or duration of LRC. However, patients in higher exposure subgroups showed a longer duration of LRC. In summary, integration of preclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, popPK, and E-R analyses support the RP3D selection of xevinapant at 200 mg/day administered on days 1-14 every 3 weeks with concomitant CRT, allowing for successive dose reductions to 150 mg and 100 mg for management of toxicities. Citation Format: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan. Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5424.

The Addition of Caulerpa racemosa Extract in Feed on Clinical Sign and Intestinal Histopathological Profile of Whiteleg Shrimp after Infected by Vibrio parahaemolyticus

The purpose of this study was to determine the administration of Caulerpa racemosa extract in clinical sign and intestinal histopathological profile of whiteleg shrimp (Litopenaeus vannamei) after infected by Vibrio parahaemolyticus. The study was conducted using a completely randomized design (CRD) with six treatments and three replications. Shrimp were divided into six groups, two control groups without the administration of C. racemosa extract, the other four groups with the administration of C. racemosa extract with successive doses; 30 mg/kg (P1), 60 mg/kg (P2), 120 mg/kg (P3) and 240 mg/kg (P4) through feed. On the 15th day of rearing, the control group was divided into two groups: negative control (K-) was injected with PBS and then positive control (K+) and four other treatments (P1, P2, P3 and P4) were infected with V. parahaemolyticus. The results showed that intestinal damage caused by V. parahaemolyticus infection were inflammation and necrosis. The administration of C. racemosa extract had a significant effect on the histopathological profile of the whiteleg shrimp intestine. The lowest percentage of damage was found in the P4 treatment, which was 19.6% with a indication of low damage. Clinical sigs appeared at 48 hours post-infection pale hepatopancreas, empty intestines, reddened uropods and gnats. From this study, it can be concluded that the administration of C. racemosa extract to the feed at a dose of 240 mg/kg is the best dose in reducing the level of damage to the intestinal organs of whiteleg shrimp infected with V. parahaemolyticus.

Evaluation of a program for outpatient sotalol loading with physician and pharmacist monitoring

BackgroundDose-dependent QT prolongation with class III antiarrhythmics mandates close monitoring often in an inpatient setting. Outpatient sotalol loading monitor provides an alternative to patients that is cost effective and allows preservation of hospital resources. ObjectivesThe objectives for this study include assessing adverse events, assessing patient adherence to monitoring and follow-up, comparing hospital cost and resource utilization, and evaluating patient satisfaction with outpatient sotalol loading program. Practice descriptionOne pharmacist in the antiarrhythmic clinic at OhioHealth Riverside Methodist Hospital completed 3-day outpatient sotalol loads under a collaborative practice agreement. Clinic services included pharmacotherapy management, medication counseling, and device education. Practice innovationThis service allows pharmacists to provide direct patient monitoring to provide increased patient access. Evaluation methodsAll data were collected via the electronic medical record, patient journal documentation, and a patient satisfaction survey. ResultsA total of 12 patients completed outpatient sotalol loading; 10 patients started in normal sinus rhythm, and 1 patient was cardioverted during the load. No patients experienced any adverse events during the loading phase. One patient completed a successful dose increase during the loading phase. All 12 patients attended the first visit, completed baseline laboratory tests, and uploaded electrocardiograms for all 3 days. A total of 11 patients were evaluated as a cost comparison for inpatient sotalol loading. On average, outpatient loading cost was $886.30, in comparison with $7571.76 for inpatient loading (P < 0.001). A total of 10 patients completed the satisfaction survey, and all of the patients preferred to complete this in the outpatient setting. ConclusionIn this study, 12 patients safely completed outpatient sotalol loading, with an overall decrease in the cost of their care in comparison with inpatient loading. This study showed that pharmacists can serve as physician extenders to continue to provide high-quality and safe care to patients in the antiarrhythmic space.

Control of spring viremia of carp in common carp using RNA interference

In this study, the control of Carp sprivivirus, commonly known as spring viremia of carp virus (SVCV), replication in Epithelioma papulosum cyprini (EPC) cells and for the first time in common carp was investigated by using the RNA interference (RNAi) technology targeting the glycoprotein (G), matrix protein (M), and RNA-dependent RNA polymerase (L) genes. Small-interfering RNA sequences (siRNAs) were selected to target three different regions on both the SVCV-G (G-102, G-1070, and G-1456) and SVCV-M gene (M-88, M-271, and M-414). Designed specific siRNAs were investigated individually or in combinations in EPC cells. In vitro results showed that the most effective siRNAs were G-102 and M-271 that significantly reduced the virus titer in EPC cells by 1.6 logs and 1.5 logs respectively. Various combinations of the G-102 and M-271 of this study and siRNA-L-602 (targets the L-gene) from our previous study were investigated in vitro. Results showed that the most effective combination in reducing the virus replication in EPC cells was the siRNA-M-271 + L-602 combination as indicated by the significant reduction in virus titer (2.9 logs). In-vivo investigation of the siRNA-M-271 + L-602 combination by single or two successive doses in common carp challenged by IP injection of SVCV showed a significant reduction in mortality rate by 77.78% and 88.89% respectively. Results were confirmed by measuring the downregulation of SVCV-M and -L gene expression in vivo.Results of this study proved that SVCV can be controlled in common carp through targeting the SVCV-M and -L genes by using the RNAi technology that results in a significant in-vivo reduction of the SVCV replication.

Citizen Stance towards Mandatory COVID-19 Vaccination and Vaccine Booster Doses: A Study in Colombia, El Salvador and Spain.

The infections and deaths resulting from Coronavirus Disease 2019 (COVID-19) triggered the need for some governments to make COVID-19 vaccines mandatory. The present study aims to analyze the position of 3026 adults in Colombia, El Salvador, and Spain regarding the possibility of making COVID-19 vaccine mandatory and the intention to be vaccinated with the booster or possible successive doses. Data from an online survey conducted from August to December 2021 among a non-representative sample of Spanish-speaking countries were collected. Multinomial Logistic Regression Models were used. A total of 77.4% of Colombians were in favor of mandatory vaccination compared to 71.5% of Salvadorians and 65.4% of Spaniards (p < 0.000). Women and people over 65 years of age were the groups most in favor of making the vaccine mandatory (p < 0.000). A total of 79.4% said they had received a third dose or would intend to receive the third dose or future doses, if necessary, compared with 9.4% who expressed doubts and 9.9% who refused to be vaccinated or did not intend to be vaccinated. Among the measures that could be taken to motivate vaccination, 63.0% and 60.6% were in favor of requiring a negative test to enter any place of leisure or work, respectively, compared to 16.2% in favor of suspension from work without pay. The acceptance of mandatory vaccination and of third or future doses varies greatly according to sociodemographic characteristics and work environment. As such, it is recommended that policy makers adapt public health strategies accordingly.

Commentary: Machine Learning to Predict Successful Opioid Dose Reduction or Stabilization After Spinal Cord Stimulation.

Commentary: Machine Learning to Predict Successful Opioid Dose Reduction or Stabilization After Spinal Cord Stimulation.

MO970: Humoral Response After Successive Doses of Mrna Vaccine Against Sars-Cov-2 in Stable Kidney Transplant Recipients

BACKGROUND AND AIMSThe poor humoral response after vaccination against SARS-CoV-2 in kidney transplant (KT) patients led to the approval of a third dose. Recent data show an increase in the antibody titer, although lower than in the general population. Our aim is to analyze the humoral immune response after the third dose a mRNA vaccine against SARS-CoV-2 and the evolution of the antispike antibody (antiS) titers in KT recipients.METHODWe performed a prospective cohort study of stable KT patients from our center who received three doses of a mRNA vaccine from March to November 2021. KT recipients with less than 6 months after transplantation and with active oncological or hematologic disease were excluded. We determined antiS titers (Abbott SARS‐CoV‐2 IgG chemiluminescent microparticle immunoassay) at baseline, one month after the second dose and one month after the third one. We compared those KT patients who seroconverted with 2 and with 3 doses of vaccine and those who did not seroconvert. To identify risk factors for no seroconversion, a logistic regression analysis was carried out.RESULTSWe included 83 KT. Mean age was 59.3 years and 62.7% were male. The median time from KT to the first vaccine dose was 94 months and between the second and third dose median time was 4 months. Seroconversion rate was 63.8% after 2 doses and 85.5% after the third one (P < 0.001). Twelve KT did not develop antibodies (Table 1). Patients who did not seroconvert were older (P = 0.047), had a worse renal function (P = 0.009) and had fewer lymphocytes than those that developed antibodies (0.013). Besides, they almost half of them received a KT from a non-heart-beating donor (P = 0.026) and were treated with thymoglobulin in the 2 years prior to the vaccine more frequently (P = 0.007). In patients who seroconverted after 2 doses, we observed a 10-fold increase in the antiS titer after the third vaccine (82 [34–350] UI/mL versus 814 [205–2415] UI/mL; P < 0.001). No patients had neither acute rejection nor serious adverse effects. In the multivariable analysis advanced age, a worse kidney function and recent treatment with thymoglobulin were risk factors for no seroconversion (Table 1).CONCLUSIONThe third dose of a mRNA vaccine against SARS-CoV-2 significantly increased the seroconversion rate and the antiS titers in stable KT patients. Advanced age, poorer kidney function and immunosuppressive treatment are risk factors for no seroconversion.

Hepatoprotective effect of a Novel Functional Drink based on Ecuadorian Plant Species

Liver diseases are considered a severe public health problem involving disorders that alter liver function. Since the liver plays an essential role in the metabolism and detoxification of substances that enter the organism, it is susceptible to damage caused by xenobiotic agents such as viruses, alcohol, and drugs. Acetaminophen is an over‐the‐counter drug widely used as an antipyretic and analgesic. It is safe at therapeutic doses, but it is easily overused, causing severe liver diseases. In a previous study, our investigation group developed a functional drink from the aqueous extracts of Ilex guayusa, Vernonanthura patens, and cocoa husks. This combination presented various bioactive compounds with antioxidant properties that could help reduce oxidative stress in pathologic conditions. For the above mentioned, the study's objective was to evaluate the hepatoprotective effect of the beverage through an in vivo test. Male mice were treated with two formulations (pre‐formulated and microencapsulated) of the functional drink in three concentrations for seven days as a preventive oral treatment. After that, mice were induced to liver damage at a single intraperitoneal dose of acetaminophen (250 mg/kg of body weight). The evaluation was based on the liver damage biomarkers, ALT, and AST; anatomopathological studies were also evaluated. The results showed that the best formulation as an oral pre‐treatment was the pre‐formulated. The pre‐formulated beverage attenuated the injury caused by the acetaminophen by inhibiting serum ALT and AST activities and reducing liver macro and microscopic liver alterations. The successful doses were at 250 and 1000 mg/kg b.w. The microencapsulated did not present adequate liver protection at any doses evaluated because it has no statistical difference with the toxic model group.In conclusion, the present study demonstrated for the first time that the functional drink effectively prevented acetaminophen‐induced liver injury in vivo. Our data indicated that the pre‐formulated was the most effective pre‐treatment to attenuate the hepatic injury. These results suggested that this beverage possessed antioxidative activity that likely contributed to its protective effect against acetaminophen liver damage.*Corresponding Author: Orellana‐Manzano Andrea, email: akorella@espol.edu.ec

Machine Learning to Predict Successful Opioid Dose Reduction or Stabilization After Spinal Cord Stimulation.

Spinal cord stimulation (SCS) effectively reduces opioid usage in some patients, but preoperatively, there is no objective measure to predict who will most benefit. To predict successful reduction or stabilization of opioid usage after SCS using machine learning models we developed and to assess if deep learning provides a significant benefit over logistic regression (LR). We used the IBM MarketScan national databases to identify patients undergoing SCS from 2010 to 2015. Our models predict surgical success as defined by opioid dose stability or reduction 1 year after SCS. We incorporated 30 predictors, primarily regarding medication patterns and comorbidities. Two machine learning algorithms were applied: LR with recursive feature elimination and deep neural networks (DNNs). To compare model performances, we used nested 5-fold cross-validation to calculate area under the receiver operating characteristic curve (AUROC). The final cohort included 7022 patients, of whom 66.9% had successful surgery. Our 5-variable LR performed comparably with the full 30-variable version (AUROC difference <0.01). The DNN and 5-variable LR models demonstrated similar AUROCs of 0.740 (95% CI, 0.727-0.753) and 0.737 (95% CI, 0.728-0.746) ( P = .25), respectively. The simplified model can be accessed at SurgicalML.com . We present the first machine learning-based models for predicting reduction or stabilization of opioid usage after SCS. The DNN and 5-variable LR models demonstrated comparable performances, with the latter revealing significant associations with patients' pre-SCS pharmacologic patterns. This simplified, interpretable LR model may augment patient and surgeon decision making regarding SCS.