Injection Site Research Articles

Adverse events following immunization of mRNA-1273 (Moderna) booster vaccine in clerkship students

Two-dose primary vaccine administration was the best strategy to reduce the prevalence and severity of COVID-19. Improved immunity and antibody response to the new variant virus by administering a booster vaccine is needed. Health workers are the main priority for administering the mRNA-1273 (Moderna) booster vaccination in Indonesia. This vaccine has high effectiveness, and safety, however, data and evaluation of adverse events following immunization (AEFI) is required. This study aimed to determine the AEFIs of mRNA-1273 booster vaccination in clinical clerkship students as an early adult age group. The research design was a repeated cross-sectional study using purposive sampling technique. There were 214 subjects who met the requirements. Subject filled out an online questionnaire containing evaluation of AEFIs. The most local AEFIs symptoms were pain at the injection site (79.0%), while the common systemic symptoms were headache, drowsiness, weakness, and fever (37.4%; 26.2%; 9.8%; 9.3%). Most AEFIs were felt within 30 minutes to three days. No respondents required hospitalization, experienced anaphylactic shock, became disabled, or died. The AEFIs did not have a significant relationship with gender, history of allergies, co-morbidities, or history of COVID-19. This information is used as a preventive or educational effort to support implementation vaccine in Indonesia.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). Some questions were answered by a limited number of people, and their responses may not be representative. Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

Determining the Safety and Tolerability of Rapid Administration of Undiluted Intravenous Levetiracetam in Pediatrics.

Objective: Levetiracetam is widely used in the emergency setting. Safety and tolerability of undiluted levetiracetam is prevalent in adults but is limited in pediatrics. The purpose is to determine the safety and tolerability of rapid administration of undiluted levetiracetam in pediatric patients. Methods: A retrospective, single-center, observational study was conducted in pediatric patients who received undiluted levetiracetam intravenous push. The primary outcome was adverse reactions, extravasation, need for intravenous line replacement, and discontinuation due to adverse reactions. The secondary outcome was turnaround time between ordering and administering first doses. Results: One hundred fourteen patients were included. Injection site reactions occurred in 7 patients. Extravasation occurred in 4 patients. Two patients required intravenous line replacement. There were no adverse events leading to discontinuation of levetiracetam. No difference was seen in the time from order to administration. Conclusion: Rapid administration of undiluted levetiracetam in pediatric patients was safe and well tolerated.

Cabotegravir + Rilpivirine Long-Acting: Overview of Injection Guidance, Injection Site Reactions, and Best Practices for Intramuscular Injection Administration

Abstract Background Cabotegravir (CAB) + rilpivirine (RPV) dosed monthly or every 2 months is a complete long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Across the Phase 3/3b trials, the most frequently reported adverse events were injection site reactions (ISRs). Methods We present pooled ISR characteristics and outcomes for participants receiving CAB+RPV LA through Week 96 of the FLAIR and ATLAS-2M studies, and survey results from healthcare providers (HCPs) giving injections (e.g. injectors) in the ATLAS, FLAIR, and ATLAS-2M studies to determine optimal injection techniques. Surveys were anonymous, self-administered online questionnaires that queried provider demographics, injection experience, and techniques to minimize pre-/post-injection discomfort. Data were summarized using descriptive statistics. Results Overall, 8453 ISRs were reported by 801 participants receiving ≥1 injection of CAB LA/RPV LA. Most ISRs were mild to moderate in severity (Grade 1–2, 99%), with a median (interquartile range) duration of 3 days (2–4), and rarely led to withdrawal (2%). Surveys were completed by 181 HCPs across 113 sites. Pushing the intramuscular injection at slow speed (66%), bringing the medication to room temperature (58%), and relaxing the gluteus muscle before injecting (53%) were ranked as effective pre-injection/injection procedure practices for minimizing pain. Most injectors (60%) indicated that a prone position provided optimal patient comfort, and 41% had no preference on injection medication order. Conclusions Taken together, the data demonstrating favorable tolerability with CAB+RPV LA injections over the long term and simple techniques routinely used by injectors to help optimize the administration of CAB+RPV LA injections.

Safety and Immunogenicity of the Live Attenuated Varicella Vaccine in Vietnamese Children Aged 12 Months to 12 Years: An Open-Label, Single-Arm Bridging Study

Objective: This study aims to evaluate the safety and immunogenicity of the SKYVaricella vaccine in healthy Vietnamese children aged 12 months to 12 years. Methods: This open-label, single-arm study involved 201 children divided into two groups: 60 children aged 12 months to 5 years and 141 children aged 6 to 12 years. Safety was assessed through immediate reactions, solicited adverse events within 7 days, and unsolicited events up to Day 42. Immunogenicity was evaluated by seroconversion rates (SCR) and geometric mean titer (GMT) increments using fluorescent antibody-to-membrane antigen (FAMA) on the day of vaccination (D0) and 42 days after vaccination (D42). Results: All participants completed the follow-up. Immediate adverse events included pain (8.0%), redness (8.0%), and swelling (20.9%) at the injection site. Within 7 days, pain (17.9%) and swelling (12.4%) were mild and self-resolving. Unsolicited adverse events were infrequent and mild. Both age groups achieved 100% SCR. GMT of varicella-zoster virus antibodies increased from 1.37 (SD 1.97) at D0 to 18.02 (SD 2.22) at D42, a 13.12-fold rise. No Grade 3 adverse events were observed. Conclusion: The SKYVaricella vaccine shows a robust immunogenic response and favorable safety profile in Vietnamese children aged 12 months to 12 years. These findings endorse its potential inclusion in pediatric vaccination programs as a reliable preventive option against varicella.

Safety and efficacy of intralesional polidocanol sclerotherapy in the treatment of plantar warts: a pilot study.

Plantar warts are common skin lesions that continue to represent a therapeutic challenge. They are still resistant to therapy and are highly recurrent, despite the diverse number of treatments available. Therapies targeting vasculature, such as pulsed dye laser, have been used successfully in the treatment of plantar warts. Polidocanol, a detergent sclerosant approved for the sclerotherapy of incompetent and dilated saphenous veins, has also been used as an off-label therapy for a wide range of skin conditions with vascular components such as hemangiomas and pyogenic granuloma. The current, open-label, prospective, pilot study aimed to evaluate the safety and efficacy of the intralesional polidocanol 3% in the treatment of plantar warts. Twenty patients (11 females and 9 males), with plantar warts, aged 12-50 years received biweekly sessions of intralesional polidocanol 3% until complete clearance or for a maximum of 6 sessions. Response to treatment was graded as complete (100% clearance), partial (50-99%), and no response (< 50%). At the end of the study, 12 (60%) patients achieved complete clearance of their warts after 1-5 sessions, 5 (25%) patients had only partial response, and 3 (15%) patients did not achieve any clearance of their warts. The procedure was largely tolerable by patients. Pain at the injection site and bruises were reported by 9 (45%) and 2 (10%) patients, respectively. Both side effects resolved spontaneously and completely within a few days. The findings of the current study suggest that intralesional injection of 3% polidocanol in biweekly sessions may be a safe, effective, and tolerable method for the treatment of plantar warts.

#2631 Efficacy and safety of Telitacicept combined with low-dose mycophenolate mofetil in IgA nephropathy

Abstract Background and Aims Currently, there is no specific agent blocking for IgA nephropathy. The KDIGO guideline recommends basic treatment with renin-angiotensin-aldosterone system (RAAS) antagonists. MMF can be used for Chinese patients. Telitacicept is a fusion protein composed of transmembrane activator and calcium modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. Telitacicept (240 mg qw ih) treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This study intends to observe the efficacy of Telitacicept (160 mg qw ih) combined with low-dose MMF in the treatment of IgA nephropathy. Method Retrospective analysis involving all biopsy proven IgA nephropathy patients with complete clinical data in our department. After RAAS inhibitor treatment for 3 months, the patient's urinary protein more than 0.75 g/24 h, he or she was given Telitacicept (160 mg qw) combined with Mycophenolate mofetil (1 g, twice a day) was treated for 6 months, and follow-up for 6-12 months. The quantification of 24-hour urinary protein and immunity functional, renal function was observed. Results 25 patients with IgA nephropathy confirmed by renal biopsy were enrolled, 14 males and 11 females, aged 34.32 ± 9.68 years’ old, 3 patients with Lee's grade II, Grade III 17 patients, Grade IV 3 patients, and Grade V 2 patients. For Oxford classification, there were 3 cases with M0, 22 cases with M1 lesions, 20 cases with E0, 5 cases with E1 lesions, 1 case with S0, 24 cases with S1 lesions, 10 cases with T0, 15 cases with T1 lesions, and 17 cases with C0, 8 cases with C1 lesions. The patient's urine protein quantification was 2.52 ± 1.82 g before treatment, after Telitacicept and MMF treatment for 2 months, the proteinuria was 1.05 ± 0.55 g (compared with that before treatment, P = 0.0004), and at 4 months, it was 0.71 ± 0.39 g (compared with that before treatment, P &amp;lt; 0.0001), 0.53 ± 0.31 g at 6 months (compared with than before treatment, P &amp;lt; 0.0001). And the 24-hour urine protein quantification of 13 patients was all lower than 0.5 g/24 hours. The renal function of all patients was stable during the observation period. The serum creatinine before treatment was 83.16 ± 21.85 μmol/L and it was 81.88 ± 19.48 μmol/L (P = 0.83) after 6 months. There were no patients with worsening renal function after treatment. Among them, the renal function of 3 patients was better than that after treatment. During follow-up period for 6- to 12-month, the patient did not develop any pulmonary infection requiring for hospitalization or other infections. Some patients experienced adverse reactions such as pain at the site of injection, but no patient discontinued treatment due to adverse reactions. Conclusion Telitacicept combined with low-dose mycophenolate mofetil is a alternative method for the treatment of IgA nephropathy. It is more effective than mycophenolate mofetil or Telitacicept use alone, and with fewer adverse reactions, especially with S or C lesions of Oxford classification. This is an observational retrospective study with a few cases, it's worthy further randomized clinical study to prove.

Immunogenicity of 2 therapeutic mosaic HIV-1 vaccine strategies in individuals with HIV-1 on antiretroviral therapy

Mosaic HIV-1 vaccines have been shown to elicit robust humoral and cellular immune responses in people living with HIV-1 (PLWH), that had started antiretroviral therapy (ART) during acute infection. We evaluated the safety and immunogenicity of 2 mosaic vaccine regimens in virologically suppressed individuals that had initiated ART during the chronic phase of infection, exemplifying the majority of PLWH. In this double-blind, placebo-controlled phase 1 trial (IPCAVD013/HTX1002) 25 ART-suppressed PLWH were randomized to receive Ad26.Mos4.HIV/MVA-Mosaic (Ad26/MVA) (n = 10) or Ad26.Mos4.HIV/Ad26.Mos4.HIV plus adjuvanted gp140 protein (Ad26/Ad26+gp140) (n = 9) or placebo (n = 6). Primary endpoints included safety and tolerability and secondary endpoints included HIV-specific binding and neutralizing antibody titers and HIV-specific T cell responses. Both vaccine regimens were well tolerated with pain/tenderness at the injection site and fatigue, myalgia/chills and headache as the most commonly reported solicited local and grade 3 systemic adverse events, respectively. In the Ad26/Ad26+gp140 group, Env-specific IFN-γ T cell responses showed a median 12-fold increase while responses to Gag and Pol increased 1.8 and 2.4-fold, respectively. The breadth of T cell responses to individual peptide subpools increased from 11.0 pre-vaccination to 26.0 in the Ad26/Ad26+gp140 group and from 10.0 to 14.5 in the Ad26/MVA group. Ad26/Ad26+gp140 vaccination increased binding antibody titers against vaccine-matched clade C Env 5.5-fold as well as augmented neutralizing antibody titers against Clade C pseudovirus by 7.2-fold. Both vaccine regimens were immunogenic, while the addition of the protein boost resulted in additional T cell and augmented binding and neutralizing antibody titers. These data suggest that the Ad26/Ad26+gp140 regimen should be tested further.

#1170 Efficacy and safety of telitacicept in IgA nephropathy: a real-world study

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and the specific therapeutic methods are limited in IgAN. Telitacicept is a humanized fusion protein composed of a transmembrane activator and calcium-modulating cyclophilin ligand interactor receptor and human IgG. This study was designed to evaluate the efficacy and safety of telitacicept in adult patients with IgAN in a real-world study. Method Biopsy-proven IgAN patients with 24-hour proteinuria greater than 0.5 g/day who received telitacicept 240 mg once a week were recruited in this study and 1:1 matched with patients who received supportive treatment only or immunosuppressive treatment by propensity score matching. The primary outcome was the change from baseline in 24-hour proteinuria over the 3-month follow-up. Results Twenty-one patients in each group were enrolled. The mean eGFR was 80.1 ml/min/1.73 m2, and the median 24-hour urine protein level was 1.48 g/day. At the end of the 3-month follow-up period, telitacicept reduced median proteinuria by 0.72 g/d (54.6%) from baseline, compared with a reduction of 0.18 g/d (20%) in the supportive treatment group (P &amp;lt; 0.001), and 1.12 g/d (72.1%) in the immunosuppressive treatment group (P = 0.814). Preserved eGFR levels were observed in the telitacicept group (1.9 ml/min/1.73 m2 [4.3%]), while the eGFR level declined in the supportive treatment group (- 2.9 ml/min/1.73 m2 [- 5.8%]) and immunosuppression group (- 6.1 ml/min/1.73 m2 [- 8.4%]). No serious adverse events were observed in the telitacicept treatment group. Injection site reactions were more prevalent in the telitacicept group (8/21 [38.1%]), meanwhile immunosuppression group had more respiratory tract infections (7/21, [33.3%]). Conclusion Telitacicept can reduce proteinuria in patients with IgAN and showed a favourable safety profile in patients with IgAN.

Efficacy and Safety of Botulinum Toxin in the Management of Temporomandibular Symptoms Associated with Sleep Bruxism: A Systematic Review

Sleep bruxism, characterized by involuntary grinding or clenching of teeth during sleep, poses significant challenges in management due to its potential to induce temporomandibular joint disorders (TMDs) and other related symptoms. The use of Botulinum toxin Type A (BoNT-A), also known as Botox®, has been proposed as a therapeutic intervention. This systematic review aims to evaluate the efficacy and safety of BoNT-A in the management of sleep bruxism, focusing on pain reduction, improvement in jaw function, reduction in bruxism episodes, and the incidence of adverse effects. An exhaustive search was conducted across PubMed, Scopus, and Embase databases up to January 2024, adhering to the PRISMA guidelines. Nine randomized clinical trials (RCTs) involving 137 participants were analyzed for efficacy and safety outcomes. The studies demonstrated a significant reduction in mean pain scores (from 7.1 to 0.2 at 6 months and 1 year post-treatment in one study) and a notable decrease in the number of bruxism events (from 4.97/h to 1.70/h in the BoNT-A group in another study). Additionally, improvements were observed in jaw stiffness and total sleep time. Adverse effects varied but were generally mild and transient, including injection site pain in 20% of participants in one study and cosmetic changes in smile in 15.4% of patients in another. These findings suggest that BoNT-A injections may provide some benefits for treating nocturnal bruxism, potentially reducing TMD symptoms like pain and improving jaw function. However, these findings are preliminary due to variability in study designs and the absence of detailed statistical analysis.

#1003 Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of AZD2373, an antisense oligonucleotide targeting APOL1

Abstract Background and Aims APOL1 mediated kidney disease (AMKD) is associated with toxic gain of function variants in people of African ancestry carrying the high-risk APOL1 genotypes (G1 and G2). APOL1 protein is part of the innate immune system but not considered essential. AZD2373, an antisense oligonucleotide that targets APOL1 mRNA to reduce its protein synthesis, is in development for AMKD. In genomic APOL1-transgenic mice, AZD2373 reduced APOL1 expression in kidney and liver, reduced plasma APOL1 protein concentration, and prevented development of IFN-γ induced proteinuria in high-risk genotype mice. In a single ascending dose study (NCT04269031), AZD2373 was well tolerated. We assessed the safety and tolerability of AZD2373 in a multiple ascending dose study including pharmacokinetics, and pharmacodynamic effect on APOL1 plasma protein levels. Method In this phase 1, randomized, single-blind, placebo-controlled study (NCT05351047) in healthy male volunteers of West African ancestry, participants were enrolled after a pre-screening study where they were genotyped for APOL1 prospectively; 18 participants had either 1 copy or 2 copies of the G1/G2 APOL1 high-risk allele. Low, medium and high dose cohorts each with 8 participants each receiving six weekly subcutaneous injections of either AZD2373 (n = 6) or placebo (n = 2) and were subsequently followed up for 9-weeks post-last dose. The primary objective was safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD2373. Results In total, 24 participants were randomized and completed the study. No major safety and tolerability concerns were reported up to the highest dose of AZD2373 administered. The most common adverse event was injection site reactions which were dose-dependent, mild to moderate in severity and did not lead to treatment discontinuation. After dosing, AZD2373 had a rapid distribution phase (hours) and prolonged elimination phase (days to weeks). Clearance was similar across dose levels after single and repeated dosing, and the renal contribution to overall clearance was minimal. Exposure generally increased in a dose proportional manner. Plasma APOL1 was knocked down in a dose dependent manner (Figure). Conclusion Repeated doses of AZD2373 were safe and well tolerated, reducing plasma APOL1 concentrations in a dose- and time-dependent manner in healthy males of West African ancestry.

#2042 Efficacy and safety of telitacicept in IgA nephropathy: a retrospective study

Abstract Background and Aims Telitacicept is a novel fusion protein composed of a recombinant transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor fused with the fragment crystallizable (Fc) region of human immunoglobulin G (IgG). Telitacicept inhibits the differentiation of immature B cell and survival of long-lived plasma cells by neutralizing the activity of B Lymphocyte Stimulator (BlyS) and A Proliferation-Inducing Ligand (APRIL). It was approved for the treatment of patients with Systemic Lupus Erythematosus (SLE) in China in March 2021. Given that BlyS/APRIL overexpression has also been identified in IgA nephropathy (IgAN), telitacicept is in clinical trials for the treatment in IgAN. In this study, we aim to retrospectively evaluate the efficacy and safety of telitacicept in patients with IgAN. Method In this retrospective study, 27 patients with primary IgAN were enrolled from Nephrology Department of Renmin hospital of Wuhan university in China from February 2022 to March 2023. Patients were administered 160 mg telitacicept by subcutaneous injection based on the previous treatment once a week at least 4 weeks, and were followed up. Adults 20–75 years of age who met the following criteria were included: biopsy-proven primary IgAN and 24-hour proteinuria &amp;gt;0.75 g. Patients were excluded if they had secondary causes of IgAN, 24 h proteinuria &amp;lt;0.75 g or immunocompromised state. Changes in proteinuria, serum creatinine, estimated glomerular filtration rate (eGFR), serum immunoglobulins, complement protein (in blood serum), albumin, urine erythrocyte, blood leukocyte and hemoglobin were analyzed during treatment. Key assessment time points were at 2, 4, 8, 12, 16 and 24 weeks after the first administration. Results In this study, duration of telitacicept exposure ranged from 4 weeks to 32 weeks, the median of which was 16 weeks. After administration of telitacicept, baseline 24 h proteinuria of 3.37 g/d decreased to 1.05 g/d at the Week 24 (z = −4.46, p &amp;lt; 0.05), with reductions statistically significant by Week 4. During telitacicept treatment, the median eGFR showed stable trend without sudden decline. Compared to the baseline eGFR of 68.34 ml/(min 1.73 m2), the eGFR at Week 24 was 72 ml/(min 1.73 m2). Changes in immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) all showed downward trend while complement protein 3 (C3) and complement protein 4 (C4) maintained stable trend. Specifically, IgA decreased from 2.51 g/L at baseline to 1.41 g/L at Week 24, there was a significant reduction by Week 4 (P = 0.001). The median of IgG decreased from 8.31 g/L at baseline to 6.71 g/L at Week 24, with reductions statistically significant by Week 4 (P = 0.008). IgM decreased significantly at Week 2 from baseline of 1.13 g/L to 1.05 g/L (P = 0.017) and was 0.64 g/L at Week 24. The median C3 was stable from baseline to Week 24 (0.92 g/L, 0.87 g/L, respectively), and C4 were 0.22 g/L and 0.23 g/L, in order. Patients had a significant increase in albumin from baseline to Week 2 (P = 0.009) and the Week 24. (36.7 g/L, 37.1 g/L and 41.8 g/L, respectively). Conversely, there was a continuous reduction in urine erythrocyte, from baseline of 62.46/μL to 7.68/μL at Week 24. There remained stable in blood leukocyte from baseline to Week 24 (8.48 × 109/L, 8.67 × 109/L, respectively), with no significant changes. By the end of the study, 10/27 patients was in complete remission (CR) and 8/27 patients had achieved partial remission (PR). The overall remission rate of primary IgAN with telitacicept treatment reached 67%. Telitacicept was generally well tolerated in patients with IgAN in this study. No treatment-emergent adverse events (AEs) occurred in all 27 patients, such as respiratory tract infection, urinary tract infections and injection site allergic. Conclusion In conclusion, based on the retrospective analysis with a small sample, telitacicept, a novel BLyS/APRIL dual inhibitor, effectively decreases proteinuria in IgAN with stable renal function. In addition, it demonstrates a favorable safety profile in patients. The data are supportive of further study with telitacicept in IgAN.

Lack of awareness of secondary rheumatic prevention in preoperative candidates for mitral valve surgery - alarming situation.

We conducted this study to assess the compliance with secondary rheumatic prophylaxis among preoperative patients with rheumatic mitral valve disease undergoing valvular heart surgery at a tertiary care cardiac hospital in a developing country. This is a descriptive cross-sectional study conducted at a tertiary care cardiac hospital in Karachi, Pakistan. The inclusion criteria encompassed patients of any sex, aged between 18 and 80 years, who had been diagnosed with rheumatic mitral valve disease through transthoracic echocardiography and had undergone valvular heart surgery. The level of compliance with secondary rheumatic prophylaxis and barriers toward noncompliance was assessed during routine preoperative interview session. This preventive measure plays a crucial role in reducing the progression of the disease and improving patient outcomes. Out of the 239 patients included in the study, 125 (52.3%) were females, with a mean age of 38.8 ± 11.8 years. The majority of patients (88.7%) came from rural areas. Among the patients, 79 (33.1%) received rheumatic prophylaxis, while 160 (66.9%) did not adhere to it regularly. The common barriers for receiving rheumatic prophylaxis were non availability (41.0%) and nonaffordability (40.6%). Additionally, 28.0% of patients had lacked awareness of the importance of rheumatic prophylaxis, and 2.5% expressed fear of injection site pain and subsequent symptoms. A concerning level of noncompliance with secondary rheumatic prophylaxis was observed. The barriers identified in patients who did not receive rheumatic prophylaxis were primarily related to affordability, availability, lack of awareness, and fear of injection site pain and subsequent symptoms.

Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy

Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA1 mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granule cell layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, which might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we performed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dynactin Subunit 2 (Dctn2) interaction was shared across all PFF conditions, and NCK Associated Protein 1 (Nckap1) and Adaptor Related Protein Complex 3 Subunit Beta 2 (Ap3b2) were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

Combined Regional Approach of Talimogene laherparepvec and Radiotherapy in the Treatment of Advanced Melanoma

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte–macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan–Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0–58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1–not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0–NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4–26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7–NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues.

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale technology and positive experience of mRNA immunization sparked the development of antiviral and anti-cancer mRNA vaccines as well as therapeutic mRNA agents for genetic and other diseases. To facilitate mRNA delivery, lipid nanoparticles (LNPs) have been successfully employed. However, the diverse use of mRNA therapeutic approaches requires the development of adaptable LNP delivery systems that can control the kinetics of mRNA uptake and expression in target cells. Here, we report effective mRNA delivery into cultured mammalian cells (HEK293T, HeLa, DC2.4) and living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or the newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane tetrahydrochloride (2X7) cationic lipids. Using end-point and real-time monitoring of Fluc mRNA expression, we showed that these LNPs exhibited an unusually delayed (of over 10 h in the case of the 2X7-based system) but had highly efficient and prolonged reporter activity in cells. Accordingly, both LNP formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) provided efficient luciferase production in mice, peaking on day 3 after intramuscular injection. Notably, the bioluminescence was observed only at the site of injection in caudal thigh muscles, thereby demonstrating local expression of the model gene of interest. The developed mRNA delivery systems hold promise for prophylactic applications, where sustained synthesis of defensive proteins is required, and open doors to new possibilities in mRNA-based therapies.

Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60–74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials.

To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.

Safety and immunogenicity of COReNAPCIN, a SARS-CoV-2 mRNA vaccine, as a fourth heterologous booster in healthy Iranian adults: A double-blind, randomized, placebo-controlled, phase 1 clinical trial with a six-month follow-up

The recurrent COVID-19 infection, despite global vaccination, highlights the need for booster doses. A heterologous booster has been suggested to enhance immunity and protection against emerging variants of concern of the SARS-CoV-2 virus. In this report, we aimed to assess the safety, and immunogenicity of COReNAPCIN, as a fourth booster dose after three doses of inactivated vaccines. MethodsThe study was conducted as a double-blind, randomized, placebo-controlled phase 1 clinical trial of the mRNA-based vaccine candidate, COReNAPCIN. The vaccine was injected as a heterologous booster in healthy Iranian adults aged 18–50 who had previously received three doses of inactivated SARS-CoV-2 vaccines. In the study, 30 participants were randomly assigned to receive either COReNAPCIN in two different doses (25 µg and 50 µg) or placebo. The vaccine candidate contained mRNA encoding the complete sequence of the pre-fusion stabilized Spike protein of SARS-CoV-2, formulated within lipid nanoparticles. The primary endpoint was safety and the secondary objective was humoral immunogenicity until 6 months post-vaccination. The cellular immunogenicity was pursued as an exploratory outcome. ResultsCOReNAPCIN was well tolerated in vaccinated individuals in both doses with no life-threatening or other serious adverse events. The most noticeable solicited adverse events were pain at the site of injection, fatigue and myalgia. Regarding the immunogenicity, despite the seroprevalence of SARS-CoV-2 antibodies due to the vaccination history for all and previous SARS-CoV-2 infection for some participants, the recipients of 25 and 50 µg COReNAPCIN, two weeks post-vaccination, showed 6·6 and 8·1 fold increase in the level of anti-RBD, and 11·5 and 21·7 fold increase in the level of anti-spike antibody, respectively. The geometric mean virus neutralizing titers reached 10.2 fold in the 25 µg group and 8.4 fold in 50 µg group of pre-boost levels. After 6 months, the measured anti-spike antibody concentration still maintains a geometric mean fold rise of 2.8 and 6.3, comparing the baseline levels in 25 and 50 µg groups, respectively. Additionally, the significant increase in the spike-specific IFN-ϒ T-cell response upon vaccination underscores the activation of cellular immunity. ConclusionCOReNAPCIN booster showed favorable safety, tolerability, and immunogenicity profile, supporting its further clinical development (Trial registration: IRCT20230131057293N1).

Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.

Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran. Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.