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Aim: To study safety, efficacy and weight loss with ADO09, a co‐formulation of insulin A21G and pramlintide, in type 1 diabetes. Materials and Methods: A randomized, two‐arm ambulatory 16‐week study compared ADO09 with insulin lispro in 80 participants with type 1 diabetes. We compared changes of weight, glycated haemoglobin, glycaemic patterns during continuous glucose monitoring, and insulin doses at baseline and at the end of treatment. Results: A significant and continuing weight loss, the primary endpoint, was observed with ADO09 compared with lispro as prandial insulin. In the whole group, the weight loss with ADO09 relative to lispro was 2.1 kg. Glycaemic control was relatively good (7.7% mean glycated haemoglobin) in both groups and did not change during treatment. Prandial insulin doses were reduced by 21% in the ADO09 group, whereas basal insulin dosage was not modified. Gastrointestinal symptoms were more frequent with ADO09, but no clear difference in hypoglycaemia was observed. Conclusions: These results extend previous observations on the efficacy and safety of this insulin/pramlintide co‐formulation. They show a beneficial effect on weight, using less mealtime insulin and without increased hypoglycaemia. [ABSTRACT FROM AUTHOR]

Objective: To systematically evaluate the efficacy of subcutaneous tocilizumab in the treatment of patients with severe COVID-19 and provide evidence for the rational use of subcutaneous tocilizumab in patients with severe COVID-19. Methods: This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched the Cochrane Library, PubMed, Embase, CNKI, SinoMed, and Wanfang Medical Network electronic databases up to 11 January 2023 to identify relevant studies. To obtain the most recent clinical studies of subcutaneous injection of tocilizumab for the treatment of patients with severe COVID-19, we also searched the preprint platforms medRxiv and ChinaXiv. Furthermore, we searched ClinicalTrials.gov for relevant unpublished studies. The studies were screened based on the PICOS principle. The included studies were classified and evaluated for quality based on research type. The RevMan 5.3 software was used to conduct the meta-analysis, and a descriptive analysis was performed to examine relevant outcome indicators. Results: Five observational studies were obtained, involving a total of 498 patients (240 patients in the subcutaneous injection group and 258 patients in the intravenous injection group). All of the studies were of the highest quality. The meta-analysis of the included studies revealed that the mortality rate of patients who received subcutaneous tocilizumab to treat COVID-19 was not significantly higher than that of the intravenous injection group [23.3% (45/193) vs. 18.4% (39/212), RD = 0.06, 95% CI = − 0.01 ~ 0.13, P = 0.11]. Furthermore, there was no significant difference in the proportion of patients requiring mechanical ventilation between the two groups [24.5% (35/143) vs. 22% (35/159), RD = 0.03, 95% CI = − 0.07 ~ 0.12, P = 0.56]. Conclusions: The meta-analyses do not provide evidence that subcutaneous and intravenous tocilizumab formulations for the treatment of severe COVID-19 infection differ regarding their effectiveness. Considering that the meta-analyses cannot replace an appropriately powered non-inferiority study, subcutaneous formulations still need to be used with caution and only when intravenous formulations are in short supply. At present, there is a lack of randomized controlled trials of subcutaneous injection of tocilizumab for the treatment of severe COVID-19, and more clinical research should be conducted. [ABSTRACT FROM AUTHOR]

Background: Eyelid surgery is one of the top five aesthetic procedures. It is performed to improve both appearance and function, but intraoperative bleeding leads to adverse events which perturb patients. The objective of this study was to demonstrate the efficacy of TXA combined with epinephrine in decreasing intraoperative blood loss and postoperative inflammation. Methods: This prospective randomized control trial was performed on the 30 eyelids of 15 patients who underwent upper blepharoplasty. One of each patient's eyes was randomly assigned to the TXA group, and the other eye was in the control group. Eyes in the TXA group were given 2% lidocaine with epinephrine (1:100000) mixed with TXA (50 mg/ml) in 1:1 mixture subcutaneously as a local anesthetic. The eyes in the control group received 2% lidocaine with epinephrine (1:100000) diluted with normal saline in 1:1 mixture. Intraoperative blood loss and postoperative swelling were compared between the two groups. Results: Intraoperative blood loss was significantly higher in the TXA group [4.86 (1.83) ml] than it was in the control group [2.53 (1.49) ml] (p < 0.001). There was no statistically significant difference between the two groups in operative time (p = 0.645), pain score (p = 0.498), lid crease (p = 0.548), or MRD1 (p = 0.626). On postoperative day 7, there was no difference in lid crease (p = 0.879), MRD1 (p = 0.463), pain score (p = 0.934), or ecchymosis (p = 0.976) between two groups. Conclusions: TXA in lidocaine with epinephrine was found to increase intraoperative bleeding compared to lidocaine with epinephrine alone, but there was no difference in postoperative swelling or ecchymosis. TXA combined with lidocaine and epinephrine injected subcutaneously should be avoided until additional relevant data are obtained. Further drug interaction study is needed. Level of Evidence II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Aims: With daily subcutaneous low-molecular-weight heparin (LMWH) injections for long periods, there is a high risk of local side effects, such as pain, bruising, and hematoma. This study aimed to compare the impact of cold application on post-injection pain, bruising, and hematoma in patients receiving subcutaneous LMWH following urologic surgery. Methods: This was a single-blind, randomized control trial. Urology inpatients were randomly assigned to three groups; Group 1: cold application for 2 min before injection, Group 2: cold application for 5 min before injection, and Group 3: control group with no cold application. Post-injection pain was assessed immediately after injection. Bruising and hematoma were assessed at 48th and 72nd hours. Results: The study included 26 patients in Group 1 (age=63.85±9.89 years; male=84.6%), 26 patients in Group 2 (age=64.54±11.66 years; male=80.8%), and 26 patients in Group 3 (age=65.65±11.36 years; male=88.5%). The pain scores in Groups 1 (11.58±12.06) and Group 2 (6.08±9.11) were lower than Group 3 (28.35±20.97) (p<0.001). At the 48th hour, the frequency of bruising in Group 1 (11.5%) and Group 2 (11.5%) was lower than that in Group 3 (38.5%) (p=0.021), and the bruise size in Group 1 (4.00±1.73 mm) was lower than that in Group 3 (15.00±7.07 mm) (p=0.020). No hematomas was detected in any patient groups at the 48th and 72nd hours. Conclusions: This study showed that although cold application for 2 or 5 minutes before injection reduced pain and bruising frequency, application for 2 minutes was more effective on bruise size. [ABSTRACT FROM AUTHOR]

Background and Objectives Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. Methods In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. Results The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an E max function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. Conclusions No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks. [ABSTRACT FROM AUTHOR]

Aims: With daily subcutaneous low-molecular-weight heparin (LMWH) injections for long periods, there is a high risk of local side effects, such as pain, bruising, and hematoma. This study aimed to compare the impact of cold application on post-injection pain, bruising, and hematoma in patients receiving subcutaneous LMWH following urologic surgery. Methods: This was a single-blind, randomized control trial. Urology inpatients were randomly assigned to three groups; Group 1: cold application for 2 min before injection, Group 2: cold application for 5 min before injection, and Group 3: control group with no cold application. Post-injection pain was assessed immediately after injection. Bruising and hematoma were assessed at 48th and 72nd hours. Results: The study included 26 patients in Group 1 (age=63.85±9.89 years; male=84.6%), 26 patients in Group 2 (age=64.54±11.66 years; male=80.8%), and 26 patients in Group 3 (age=65.65±11.36 years; male=88.5%). The pain scores in Groups 1 (11.58±12.06) and Group 2 (6.08±9.11) were lower than Group 3 (28.35±20.97) (p

Abstract Introduction Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. Methods A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. Results Pharmacokinetic analysis of the drug concentration–time data showed that the mean maximum observed serum QX002N concentration (C max) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration–time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration–time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. Conclusions Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. Trial Registration www.chinadrugtirals.org.cn , CTR20220430.

Introduction: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. Methods: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. Results: Pharmacokinetic analysis of the drug concentration–time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration–time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration–time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. Conclusions: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. Trial Registration: www.chinadrugtirals.org.cn, CTR20220430. [ABSTRACT FROM AUTHOR]

Introduction: Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). Methods: The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. Results: Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0–96.3%. Similarly, MMAS score (maximum 4) was 3.8–3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0–98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was "change of treatment" (10.0%). Discussion: We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. Conclusions: Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. Trial Registration Number: Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

Abstract Introduction Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). Methods The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. Results Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0–96.3%. Similarly, MMAS score (maximum 4) was 3.8–3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0–98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was “change of treatment” (10.0%). Discussion We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. Conclusions Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. Trial Registration Number Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892 .

Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes' assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration. Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14 days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts. Results: Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3 years (range 24-80 years), and 67.4% (N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration. Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure. [ABSTRACT FROM AUTHOR]

Introduction: A new, citrate-free ixekizumab formulation, which is bioequivalent to the original formulation, was associated with significant reduction in injection site pain. This study evaluates patient satisfaction with the first injection experience of citrate-free ixekizumab in a real-world setting. Methods: A non-interventional, observational, web-based survey of adults (≥ 18 years) with psoriasis, psoriatic arthritis, or axial spondyloarthritis was conducted between August 2022 and March 2023. Patients enrolled in the Taltz US Customer Support Program were identified as receiving either the original ixekizumab or initiating citrate-free ixekizumab. Patients receiving original ixekizumab completed one survey at baseline to assess satisfaction with the formulation and one survey after switching to assess satisfaction, willingness to continue using and recommending citrate-free ixekizumab, and formulation preference. Participants previously exposed to ixekizumab completed one survey to assess their satisfaction and willingness to continue using and recommending citrate-free ixekizumab. Descriptive and comparative statistics are reported for patients that switched from original to citrate-free ixekizumab (n = 361); and descriptive statistics are reported for patients not previously exposed to ixekizumab (n = 90). Results: A total of 451 patients were included in the analysis. Significantly more patients were satisfied with their first injection with citrate-free ixekizumab compared to original ixekizumab (83.9% vs. 71.7% respectively; p = 0.0001). Almost all patients who switched from original ixekizumab were definitely or mostly willing to continue using and recommending citrate-free ixekizumab (93.9% and 93.4%, respectively). Additionally, 94.2% of patients who switched from original to citrate-free ixekizumab preferred citrate-free ixekizumab or had no preference. Three-fourths of patients not previously exposed to ixekizumab were satisfied with their first injection with citrate-free ixekizumab and 94.5% were definitely or mostly willing to continue using citrate-free ixekizumab. Conclusion: The citrate-free ixekizumab formulation was preferred and well accepted by most patients who switched from the original ixekizumab formulation. Similar findings were seen for those newly initiating citrate-free ixekizumab. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease's mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection. Synopsis: Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by infection with a novel bunyavirus (SFTSV). However, the existence of multiple SFTSV genotypes presents a significant challenge for developing therapeutic antibodies targeting SFTSV. We provided compelling evidence for the involvement of the PD-1/PD-L1 pathway in the acute infection caused by SFTSV, while demonstrating the potent inhibitory effect of our novel anti-PD1 nanobody, NbP45, against SFTSV infection in vitro and in SFTSV-infected NCG-HuPBL mouse model. During SFTSV infection, the expression of PD-1/PD-L1 in immune cells was significantly upregulated. Subcutaneous NbP45, a new nanobody developed by us, exhibited better protective efficacy than the anti-PD1 antibody drug with traditional format of whole IgG. PD-1/PD-L1 could serve as the conserved host targets for developing potential immunotherapy interventions to broadly treat SFTSV infection. Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by infection with a novel bunyavirus (SFTSV). However, the existence of multiple SFTSV genotypes presents a significant challenge for developing therapeutic antibodies targeting SFTSV. We provided compelling evidence for the involvement of the PD-1/PD-L1 pathway in the acute infection caused by SFTSV, while demonstrating the potent inhibitory effect of our novel anti-PD1 nanobody, NbP45, against SFTSV infection in vitro and in SFTSV-infected NCG-HuPBL mouse model. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nicolau syndrome is a rare adverse drug reaction, which is generated after the intramuscular, subcutaneous or intravenous application of a drug. It presents as a painful erythematous macule or plaque at the puncture site which may progress to necrosis of the skin and surrounding tissue. CLINICAL CASE: A 73-year-old female patient, with a 1-month history of appearance of an erythematous plaque, associated with intense pain in the right gluteal region. The patient related the onset of the injury to the intramuscular application of two drugs: diclofenac and dexamethasone. Two weeks after the initial consultation, the patient developed a necrotic and ulcerated plaque that was treated with dressings and topical collagenase with good clinical evolution. CONCLUSIONS: Nicolau syndrome is a rare entity associated with the application of medication. It is caused by vascular damage after drug delivery which leads to tissue ischemia and necrosis: it can affect the skin, subcutaneous cellular tissue and muscle, sometimes requiring amputation of the affected limb or even causing death. [ABSTRACT FROM AUTHOR]

Abstract Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease’s mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection.

Objective To explore the establishment of a subclinical hypothyroidism（SCH） rat model during pregnancy using total thyroidectomy and L-T4 subcutaneous injection method and evaluate the stability of the model.Methods A total of 26 female SD rats weighing 180-200 g were randomly divided into the control group（n=10） and the model group（n=16）.The control group was treated with total thyroidectomy, while the model group was treated with total thyroidectomy and postoperative subcutaneous injection of L-T4 1.0 μg/（100 g·d）.The levels of TSH,TT4 and body weight were observed at three time points: one month after operation, after total thyroidectomy+L-T410 d after operation and 13 d after pregnancy.Results One month after operation, the serum TSH level of the rats in the model group was significantly higher than that of the control group, and the difference was statistically significant（P＜0.01）.After total thyroidectomy +L-T410 d, the serum TSH level of the rates in the model group was higher than that in the control group, and the difference was statistically significant（P＜0.01）.At the 13th day of pregnancy, the serum TSH level of the rates in the model group was significantly higher than that in the control group（P＜0.01）.The serum TT4 level in the model group was lower than that in the control group one month after operation, and the difference was statistically significant（P＜0.01）.There was no statistically significant difference in serum TT4 levels of the rats in two groups after total thyroidectomy+L-T410 d（P＞0.05）.At the 13th day of pregnancy, there was no statistically significant difference in TT4 levels between the two groups（P＞0.05）.There was no significant difference in preoperative weight between the two groups（P＞0.05）.The weight of the model group was significantly lower than that of the control group after non-pregnancy surgery and drug administration, and the difference was statistically significant（P＜0.01）.At 13th day of pregnancy, the weight of model group was significantly lower than that of control group, and the difference was statistically significant（P＜0.01）.There was no significant difference in the average number of offspring between the two groups（P＞0.05）.Conclusion The method of subcutaneous injection of L-T4 can successfully establish a SCH rat model during pregnancy, with good stability.  [ABSTRACT FROM AUTHOR]

Insulinoma is a neuroendocrine tumor. It arises from the uncontrolled proliferation of pancreatic β cells. In this study, we created an insulinoma tumor model in nude mice. INS-1 cells were injected in two different ways, subcutaneously (S.C.) or intraperitoneally (I.P.). Body weight, tumor weight, and size were measured. ELISA kits were used analyze to Glucose, insulin, and CA19-9 levels in serum, pancreas, and tumor tissues. KCNN4, KCNK1, GLUT2, IR, HSP70, HSF1, and HSP90 levels were analyzed by western blotting of membrane and/or cytosolic fractions of tumor and pancreas tissue. Tumor formation occurred in nude mice, but it did not occur in Wistar albino rats. The tumor has neuroendocrine cell morphology. Insulin and CA19-9 levels increased in pancreas tissue. In tumor tissue, KCNN4 levels were higher in both membrane and cytosolic fractions, while KCNK1 levels were lower in the membrane fraction of the S.C. group. HSP70 levels were also lower in the S.C. group. In pancreas tissue, KCNK1 levels were lower in the membrane fraction of the S.C. and I.P. groups. GLUT2 levels increased in both groups according to the control group, while IR levels decreased in the S.C. group compared to the control group. However, HSF1 levels increased in the I.P. group, while HSP90 decreased in the S.C. group in pancreatic tissues. The S.C. group is a more suitable insulinoma tumor model. KCNN4, KCNK1, and HSP70 proteins may be important biomarkers in the diagnosis and treatment of insulinoma. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6–8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5–15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities. [ABSTRACT FROM AUTHOR]

Introduction: Regular, prophylactic intravenous (i.v.) FVIII can be challenging for some patients with haemophilia A. Subcutaneous (s.c.) FVIII administration could provide an alternative treatment option with greater convenience and without the complications associated with venous access. Aim: To assess the safety, pharmacokinetics (PK), bioavailability and efficacy of s.c. OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer. Methods: This was a single‐centre, prospective, open‐label, phase I/II study (NCT04046848). Previously treated male patients (≥18 years) with severe haemophilia A were eligible for the study. The primary objective of the study was to assess the safety (including immunogenicity) of OCTA101. Secondary objectives included assessments of PK, bioavailability, and the efficacy of prophylaxis. Results: Thirty patients were treated with OCTA101. FVIII inhibitors developed in five (16.7%) patients during daily prophylaxis with 40–60 IU/kg (three cases) and 12.5 IU/kg (two cases) OCTA101. The trial was therefore terminated. OCTA101 had a 2.5‐fold longer terminal half‐life compared with i.v. rFVIII, and bioavailability was 16.6%. Efficacy data at study termination indicated that daily prophylaxis with 40–60 IU/kg OCTA101 was efficacious in the absence of FVIII inhibitors. Conclusions: Despite promising PK and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors. The occurrence of inhibitors at two dose levels suggests that their development may be related to the subcutaneous route of administration. [ABSTRACT FROM AUTHOR]

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Monoclonal antibody products are an increasing portion of novel drug approvals. The labeling of initial drug approvals frequently involves body-size-based rather than fixed-dose administration regimens for adults without clear rationale for doing so. This presents challenges when prescribing these products for patients with extremes of body habitus who constitute a small portion of enrollment in pre-approval investigations. Fixed-dose regimens allow for standardized preparation with the potential to reduce the risk of calculation errors, drug waste, and make home administration more practical. Fixed-dose rather than body-size-based monoclonal antibody regimens should serve as the initial approach in early phase 1 clinical trials. [ABSTRACT FROM AUTHOR]

Background: The maintenance of nursing professional competency is essential to ensure patients' health outcomes. With the current shortage of nursing workforce, a novel approach is necessary to refresh clinical skills and update practice. Objective: This study aims to examine the effectiveness of using head-mounted display virtual reality to refresh knowledge and skills and explore nurses' perceptions towards using this technology for refresher training. Design: A pre-test post-test mixed-method experimental design was employed. Results: Participants (n = 88) were registered nurses with a diploma in nursing. The intravenous therapy and subcutaneous injection procedures were implemented using headmounted display virtual reality. The study showed significant improvement in knowledge for the procedures, cognitive absorption, online readiness, self-directed learning, and motivation for learning. In the qualitative focus group discussions, three themes were identified using thematic analyses: enjoyable way to refresh clinical knowledge; learning outside classroom and limitations in maneuver. Conclusion: Using head-mounted display virtual reality is promising in refreshing clinical skills for nurses. Training and refresher courses can explore using this novel technology, which may be a viable alternative to ensure professional competence with reduced manpower and resources used by the healthcare institution. [ABSTRACT FROM AUTHOR]

Subcutaneous injection of monoclonal antibodies (mAbs) has experienced unprecedented growth in the pharmaceutical industry due to its benefits in patient compliance and cost-effectiveness. However, the impact of different injection techniques and autoinjector devices on the drug's transport and uptake is poorly understood. Here, we develop a biphasic large-deformation chemomechanical model that accounts for the components of the extracellular matrix that govern solid deformation and fluid flow within the subcutaneous tissue: interstitial fluid, collagen fibers and negatively charged proteoglycan aggregates. We use this model to build a high-fidelity representation of a virtual patient performing a subcutaneous injection of mAbs. We analyze the impact of the pinch and stretch methods on the injection dynamics and the use of different handheld autoinjector devices. The results suggest that autoinjector base plates with a larger device-skin contact area cause significantly lower tissue mechanical stress, fluid pressure and fluid velocity during the injection process. Our simulations indicate that the stretch technique presents a higher risk of intramuscular injection for autoinjectors with a relatively long needle insertion depth. [ABSTRACT FROM AUTHOR]

Subcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests. [ABSTRACT FROM AUTHOR]

The aim of this study is to examine the most watched videos about the application of enoxaparine on Youtube in terms of quality, reliability, usefulness and comprehensiveness. The reason for examining the videos of the broadcasts on Youtube in the study is that Youtube is a digital information source that people can access easily. In the evaluation of the videos, the video power index was calculated based on both views and likes. The quality of the videos was evaluated according to the Global Quality Score-GQS score, and the reliability was evaluated according to the DISCERN scale scores. A total of 400 videos were watched in the study and analyzes were carried out with the remaining 34 videos after the exclusion criteria. 16 of these videos were uploaded by patients, 13 by healthcare professionals, and 5 by other individuals/ institutions. 25 (73.5%) of the videos contain useful information and 9 (26.5%) misleading information. According to the quality scores of the videos calculated by GQS scoring, 15 were low, 6 were medium, and 13 were high quality videos. It was determined that the reliability and comprehensiveness scores of the videos were moderate. The results of the research revealed that Youtube videos are not an adequate instructional resource regarding the quality, safety and comprehensiveness of teaching self-injection of enoxaparine. [ABSTRACT FROM AUTHOR]

Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes’ assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration.Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14 days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts.Results: Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3 years (range 24–80 years), and 67.4% (N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration.Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure.

To determine and compare the abilities of ShotBlocker and cryotherapy for reducing pain and anxiety associated with subcutaneous injections. Subcutaneous injection has been used excessively for continuous, low-dose administration of drugs. Considering that these drugs may require prolonged administration, new devices and methods of injection are needed to decrease pain and anxiety associated with repeated drug injections.

Objective To investigate the effect of quality control circle(QCC) activities in the improvement of standard subcutaneous injection of anticoagulants. Methods A QCC group was established, and factors influencing the subcutaneous anticoagulant injection were investigated and analyzed, and the PDCA procedure was adopted for decision making and countermeasures implementation. Results The standard rate of subcutaneous anticoagulant injection was increased form 55. 07% to 67. 95% after implementation of QCC activities. Conclusion The QCC is an effective management tool in improving the quality of subcutaneous anticoagulant injection and ensuring the safety and effectiveness of anticoagulation. (目的 探讨品管圈活动提高抗凝药物皮下注射规范率的效果。方法 开展问题解决型品管圈活动, 通过现状分析、原因解析, 制定了针对性对策并予以实施。结果 抗凝药物皮下注射规范率从55. 07%提高至67. 95%。结论 品管圈活动能够提高抗凝药物皮下注射规范率, 保障护理安全, 提升护理服务质量。)

Aim: To assess the safety and tolerability of subcutaneous (SC) trastuzumab (Herceptin) administered either with a single-use injection device (SID) or manually from a vial using a hand-held syringe. Methods: The ESCAPE trial (NCT02194166) included 90 women aged 18 years or older with HER2-positive early breast cancer who underwent surgical treatment and completed (neo) adjuvant chemotherapy and radiotherapy (if indicated). Patients enrolled in the study were first subjected to 4 cycles of trastuzumab IV (8 mg/kg loading dose followed by 6 mg/kg maintenance dose, q3w) prior to being randomized into groups: [A] SC trastuzumab (fixed dose 600 mg, q3w) administered through a hand-held syringe followed by 7 cycles of SC trastuzumab administered with an SID or [B] the reverse sequence. Results: Patient-reported outcomes revealed that 78 (94.0 % [95 % CI: 90.4–99.0]) out of 83 patients preferred SC trastuzumab over IV trastuzumab, among whom 28 patients indicated a strong preference. Sixteen out of 17 HCPs (94.1 %) were very satisfied with the use of SC trastuzumab, while 1/17 (5.9 %) remained uncertain. The mean time spent for IV vs. SC trastuzumab administration, including pre- and postinjection procedures, was 93.8 and 22 min, respectively. A total of 49 (54.4 %) patients reported 164 AEs. Conclusions: In this trial, SC trastuzumab was preferred over IV trastuzumab. The duration of SC trastuzumab administration was significantly shorter than that of IV trastuzumab, saving patients and HCPs time. Safety and efficacy results were consistent with other published trials and were not associated with any new safety signal.

AbstractSubcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests.

Aims: To reassess the 6‐month efficacy and to assess the 12‐month sustained efficacy of the MiniMed™ 780G advanced hybrid closed‐loop automated insulin delivery (AID) system compared to multiple daily injections plus intermittently scanned glucose monitoring (MDI+isCGM) in people with type 1 diabetes not meeting glucose targets. Methods: The ADAPT study was a prospective, multicentre, open‐label, randomized control trial in people with type 1 diabetes, with a glycated haemoglobin (HbA1c) concentration of at least 8.0% (64 mmol/mol), on MDI+isCGM therapy. After a 6‐month study phase, participants randomized at baseline to MDI+isCGM switched to AID (SWITCH) while the others continued AID therapy (SUSTAIN) for an additional 6 months. The primary endpoint of this continuation phase was the within‐group change in mean HbA1c between 6 and 12 months, with superiority in the SWITCH group and noninferiority in the SUSTAIN group (ClinicalTrials.gov: NCT04235504). Results: A total of 39 SWITCH and 36 SUSTAIN participants entered the continuation phase. In the SWITCH group, HbA1c was significantly decreased by −1.4% (95% confidence interval [CI] −1.7% to −1.1%; P < 0.001) from a mean ± SD of 8.9% ± 0.8% (73.9 ± 8.6 mmol/mol) at 6 months to 7.5% ± 0.6% (58.5 ± 6.9 mmol/mol) at 12 months. Mean HbA1c increased by 0.1% (95% CI −0.05% to +0.25%), from 7.3% ± 0.6% (56.5 ± 6.7 mmol/mol) to 7.4% ± 0.8% (57.7 ± 9.1 mmol/mol) in the SUSTAIN group, meeting noninferiority criteria. Three severe hypoglycaemia events occurred in two SWITCH participants during the continuation phase. Conclusion: ADAPT study phase glycaemic improvements were reproduced and sustained in the continuation phase, supporting the early adoption of AID therapy in people with type 1 diabetes not meeting glucose targets on MDI therapy. [ABSTRACT FROM AUTHOR]

• Preclinical studies in rats show rapid absorption and elimination of caffeine with no effect from co-administered model mAb. • Caffeine does not affect PK profiles and SQ bioavailability of the model mAb. • SQ injection of caffeine at the tested dose levels shows no safety concern. • Current studies ensure further development of caffeine as a viscosity reducing excipient for high concentration mAb formulations. Caffeine is a novel excipient that effectively reduces viscosity of high concentration mAb formulations intended for subcutaneous (SQ) delivery. Two preclinical studies were conducted in rats to evaluate pharmacokinetic (PK) parameters of caffeine as well as its effects on the PK profile of a model mAb, namely ipilimumab. Results show that SQ absorption and elimination of caffeine was rapid, with the average T max of 0.4 h and T 1/2 of 1.6 h, administered with or without ipilimumab. Furthermore, caffeine did not affect ipilimumab SQ PK profiles. Independent of caffeine concentration, ipilimumab serum T 1/2 was between 2 and 3 days, T max was between 3 and 4 days and SQ bioavailability was about 64%. In addition, SQ injection of caffeine at different dose levels showed no irritation at the injection site or adverse effects. Results from the current PK studies warrant further development of caffeine as a viscosity reducing excipient for mAb SQ formulations. [ABSTRACT FROM AUTHOR]

This article discusses a research study that examined the effects of different local cold application methods on pain and ecchymosis in subcutaneous heparin injections. The study found that using local cold packs was the most effective method in reducing pain intensity and ecchymosis. The findings suggest that these nonpharmacological methods can be used by nurses to improve patient comfort and reduce complications associated with these injections. The study was approved by the Cyprus Dr. Burhan Nalbantoglu Hospital Institutional Review Board and informed consent was obtained from the participating patients. [Extracted from the article]

Comparing the technical reliability and insulin dosing of a "do-it-yourself artificial pancreas" with a commercial hybrid closed-loop system in a "shadow-mode" scenario: An exploratory study Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study. Keywords: CSII; insulin pump therapy; subcutaneous injection; type 1 diabetes EN CSII insulin pump therapy subcutaneous injection type 1 diabetes 2780 2783 4 08/03/23 20230901 NES 230901 INTRODUCTION Do-it-yourself artificial pancreas systems (DIYAPSs) are compound devices that autonomously adjust insulin dosage in people with diabetes. However, the DIYAPS was not delivering insulin, which might have caused an overcompensation of insulin adaptions if delivered insulin doses were lower than calculated by the DIYAPS. [Extracted from the article]

Inoculation routes may significantly affect vaccine performance due to the local microenvironment, antigen localization and presentation, and, therefore, final immune responses. In this study, we conducted a head-to-head comparison of immune response and safety of inactivated rabies vaccine inoculated via intraperitoneal (IP), intramuscular (IM), subcutaneous (SC) and needle-free injection technology-based intradermal (ID) routes in ICR mice. Immune response was assessed in terms of antigen-specific antibodies, antibody subtypes and neutralizing antibodies for up to 28 weeks. A live rabies virus challenge was also carried out to evaluate vaccine potency. The dynamics of inflammatory cell infiltration at the skin and muscle levels were determined via histopathological examination. The kinetics and distribution of a model antigen were also determined by using in vivo fluorescence imaging. Evidence is presented that the vaccine inoculated via the ID route resulted in the highest antigen-specific antibody and neutralizing antibody titers among all administration routes, while IP and IM routes were comparable, followed by the SC route. Antibody subtype analysis shows that the IP route elicited a Th1-biased immune response, while SC and IM administration elicited a prominent Th2-type immune response. Unexpectedly, the ID route leads to a balanced Th1 and Th2 immune response. In addition, the ID route conferred effective protection against lethal challenge with 40 LD50 of the rabies CVS strain, which was followed by IP and IM routes. Moreover, a one-third dose of the vaccine inoculated via the ID route provided comparable or higher efficacy to a full dose of the vaccine via the other three routes. The superior performance of ID inoculation over other routes is related to longer local retention at injection sites and higher lymphatic drainage. Histopathology examination reveals a transient inflammatory cell infiltration at ID and IM injection sites which peaked at 48 h and 24 h, respectively, after immunization, with all side effects disappearing within one week. These results suggest that needle-free injection technology-based ID inoculation is a promising strategy for rabies vaccination in regard to safety and efficacy. [ABSTRACT FROM AUTHOR]

BackgroundMarzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia.ObjectivesTo investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis.MethodsThis multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24-hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48-hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30-day follow-up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation.ResultsIn the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension.ConclusionsThe data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

• Inclusion of women from two clinics enhance the transferability of the results. • The majority of women are positive towards the subcutaneous administration. • The subcutaneous administration does not meet all expectations. • Some women prefer the vaginal administration of progesterone. • Several women are interested in being included in the decision-making. The hormones used in fertility treatment come in various forms. Progesterone used for luteal phase support is often administered vaginally as either suppositories, tablets or gel. However, in Denmark the administration of progesterone as a subcutaneous injection has newly been introduced. The aim of the study was to explore patient attitudes towards and satisfaction with subcutaneous injection of progesterone versus vaginal administration of progesterone in Assisted Reproductive Technology (ART) treatments. A qualitative study with online and face to face interviews with a total of 19 women undergoing an ART treatment. Only women with at least one previous blastocyst transfer using vaginal progesterone or subcutaneous progesterone could be recruited. All participants were included from either the Fertility Clinic at Copenhagen University Hospital – Herlev and Gentofte or from the Fertility Unit at Aalborg University Hospital. The analysis resulted in four themes: (1) medication, (2) everyday life, (3) bodily experiences and (4) infertility or hope. Most informants highlighted the administration of subcutaneous progesterone only once a day and avoidance of the vaginal discharge as clear advantages. Reasons for preferring the vaginal administration were inconvenience of bringing the subcutaneous medication along and resistance to inject oneself. The findings of this study suggest that the satisfaction with the subcutaneous progesterone is generally positive. However, valuable thoughts have given insights into possible areas, which could be improved. Further, that some women prefer vaginal progesterone. The results show that the women are interested in being included in the decision-making when choosing the administration form of progesterone. [ABSTRACT FROM AUTHOR]

We assessed if there were any sex-related differences in the ability of nicotine to increase plasma corticosterone secretion after single or repeated nicotine administration. For single-dose studies, male and female mice were habituated to the test room for 1 h and injected with saline or nicotine (0.25 or 1 mg/kg, subcutaneously (s.c.)). In repeated-dosing studies, mice were injected with saline or nicotine (1 mg/kg, s.c.) once daily for six days, and, on day 7, received nicotine (1 mg/kg, s.c.). Mice were then euthanized 15 min later, and trunk blood was collected for the measurement of corticosterone, nicotine, and cotinine. Our results showed that saline or nicotine each significantly increased plasma corticosterone levels in both males and females, with a greater response in female mice. Plasma corticosterone levels were increased in male but not female mice after being treated repeatedly compared to single nicotine administration. The level of cotinine, a biomarker of nicotine use, was significantly higher in female than in male mice. Taken together, these novel findings suggest that female mice respond to nicotine and the stress of handling more than male mice and provide for the first-time quantitative data on male-female differences in nicotine-induced elevations of corticosterone and cotinine plasma levels.

Objectives: Bee venom (BV) therapy is performed by a bee sting or subcutaneous injection of BV. However, there is not much information on the effect of BV on blood parameters after entering the body. This project aimed to assess the side effects of subcutaneous BV injections in healthy rats by measuring the hematological and biochemical parameters.Methods : Various amounts of BV, including 100, 200, and 500 (μg/day), were subcutaneously injected into rats for 30 days. The results showed that BV affected the metabolism of the liver, kidney, and glands.Results : An increase in blood sugar and a decrease in other biochemical parameters, including cholesterol, triglyceride, urea, creatinine AST, ALT, ALP, and phosphorous, were observed. Results : also showed increased counts of white blood cells, neutrophils (%), and platelets and decreased levels of red cells, hemoglobin, and hematocrit.Conclusion : This study demonstrates that BV therapy in medical clinics requires routine care and testing to prevent eventual metabolic and anemia side effects.

Widespread use of subcutaneous injection for parenteral medications is likely to be related to high medication bioavailability and rapid onset of action. Correct subcutaneous injection technique and site selection are essential for nursing care quality and patient safety. The study aimed to determine nurses' knowledge and practice preferences regarding subcutaneous injection technique and administration site selection. This cross-sectional study took place between March and June 2021. This study included 289 nurses, willing to participate who worked in units performing subcutaneous injections in a university hospital in Turkey. Most nurses reported their preferred administration site for subcutaneous injections was the lateral aspects of the upper arm. More than half of the nurses did not use a rotation chart, they swabbed the skin before a subcutaneous injection, and they always pinched the skin at the injection site; 50% of nurses reported always administering subcutaneous injections at an angle of either 90 or 45 degrees. Most nurses performed an injection in less than 30 s and waited for 10 s before withdrawing the needle. They did not apply massage onto the site following the injection. Nurses' knowledge of subcutaneous injection was at a moderate level. Nurse knowledge of best practice subcutaneous injection administration and site selection could be improved in line with current evidence to improve personcentred and quality and safe care delivery. Future research should involve developing and evaluating educational strategies and practice standards to enhance nurse understanding of best practice evidence to meet patient safety goals. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the herpes zoster subunit vaccine Shingrix™ performs well in clinical trials. However, the key ingredient in its adjuvant, QS21, is extracted from rare plants in South America, so vaccine production is limited. Compared with subunit vaccines, mRNA vaccines have the advantages of faster production and not requiring adjuvants, but currently, there is no authorized mRNA vaccine for herpes zoster. Therefore, this study focused on herpes zoster subunit and mRNA vaccines. We prepared a herpes zoster mRNA vaccine and compared the effects of vaccine type, immunization route, and adjuvant use on vaccine immunological efficacy. The mRNA vaccine was injected directly into mice via subcutaneous or intramuscular injection. The subunit vaccine was mixed with adjuvants before immunization. The adjuvants include B2Q or alum. B2Q is BW006S + 2395S + QS21. BW006S and 2395S are phosphodiester CpG oligodeoxynucleotides (CpG ODNs). Then, we compared the cell-mediated immunity (CIM) and humoral immunity levels of the different groups of mice. The results showed that the immune responses of mice inoculated with the mRNA vaccine prepared in this study were not significantly different from those of mice inoculated with the protein subunit vaccine supplemented with the B2Q. The mRNA vaccine-induced immune responses following subcutaneous or intramuscular injection, and the different immunization routes did not lead to significant differences in immune response intensity. Similar results were also observed for the protein subunit vaccine adjuvanted with B2Q but not alum. The above results suggest that our experiment can provide a reference for the preparation of mRNA vaccines against herpes zoster and has certain reference significance for the selection of the immunization route; that is, there is no significant difference in the immune response caused by subcutaneous versus an intramuscular injection, so the injection route can be determined according to the actual situation of individuals. [ABSTRACT FROM AUTHOR]

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Introduction: X-linked hypophosphataemia (XLH) is a rare, genetic renal phosphate-wasting disease, resulting from excess fibroblast growth factor 23 (FGF23) activity, which has a progressive and profound impact on patients throughout life. The monoclonal anti-FGF23 antibody, burosumab, is a subcutaneous injection indicated for the treatment of XLH in children and adults. Originally, burosumab was approved to be administered by a healthcare professional (HCP), but the option of self-administration would enable patient independence and easier access to treatment. Two open-label, single-arm clinical trials, conducted in Japan and Korea, have assessed the safety and efficacy of self-administration of burosumab in both children and adults with XLH. Methods: In KRN23-003 (n = 15 children aged 1–12 years) and KRN23-004 (n = 5 children aged 3–13 years, n = 4 adults aged 21–65 years), children initially received 0.8 mg/kg of burosumab every 2 weeks and adults initially received 1.0 mg/kg of burosumab every 4 weeks. Self-administration was permitted from Week 4, and patients or carers were provided with training to inject correctly. Results: In both trials, burosumab had an acceptable safety profile with mainly mild-to-moderate adverse events. Following self-administration, no patients reported serious treatment-emergent adverse events ≥ grade 3, injection-site reactions or hypersensitivity reactions related to burosumab. Serum phosphate and active vitamin D levels increased from baseline in children and adults. Conclusions: These results indicated that the efficacy and safety of burosumab when administered either by a carer or patient are similar to that when administered by an HCP and show that self-administration is a viable option for patients with XLH. Trial Registration Numbers: NCT03233126 and NCT04308096. [ABSTRACT FROM AUTHOR]

• After subcutaneous injection administrations, local complications such as ecchymosis, hematoma, and pain can be seen at the injection site usually depending on the injection technique. • As a result of our study, ecchymosis development and pain intensity were found to be lower in the compression group than in the cold application and control groups. • In addition, ecchymosis and pain developed less in the cold application group compared to the control group. Subcutaneous administration may result in complications such as bruising and pain at the injection site. This study was performed as in order to determine the effect of cold application and compression on pain and bruising in subcutaneous heparin injection. The study was a randomized controlled trial. 72 patients were included in the study. Each patient in the sample was both experimental (cold and compression) and control groups and 3 different parts of abdomen were used for injection of each patient. The data of the research were collected by using Patient Identification Form, Subcutaneous Heparin Observation Form and Visual Analog Scale (VAS). In the study, it was observed that after heparin injection, ecchymosis developed in 16.4%, 28.8%, and 54.8% of the patients, respectively, and pain was experienced during injection in 12.3%, 43.5%, and 44.2% of the patients, respectively, on the pressure, cold application, and control site groups, and this difference was statistically significant (p<0.001). In the study, it was found that bruising size of the compression group was smaller in contrast with the other groups. When the VAS mean was examined for the groups, it was found that the patients in the compression group had lower pain than the other groups. In order to prevent complications that may arise in nurses' subcutaneous heparin injections and to increase the quality of patient care, it may be recommended to transfer the 60-second compression application after subcutaneous heparin applications to clinical applications and to conduct studies comparing compression and cold application with other applications for future studies. [ABSTRACT FROM AUTHOR]

Background: There is no description of the drivers of prescription for allergen immunotherapy (AIT) for respiratory allergic diseases. Methods: A prospective, multicentre, observational, non-interventional real-life study was performed in France and Spain for 20 months. Data were gathered using 2 different questionnaires, anonymously collected in an online platform. No names of AIT products were recorded. Multivariate analysis and unsupervised cluster analysis were performed. Results: One hundred and three physicians (50.5% from Spain and 49.5% from France) reported 1735 patients (433 in France and 1302 in Spain), 47.9% males, 64.8% adults with a mean age 26.2 years old. They suffered from allergic rhinitis (99%), allergic conjunctivitis (70.4%), allergic asthma (51.8%), atopic dermatitis (13.9%), and food allergy (9.9%). A clustering analysis based on 13 predefined relevant variables for AIT-prescription identified 5 different clusters, each of them including information regarding doctor's profile and patient demographics, baseline disease characteristics, and main AIT indication: 1) Looking at the future: focusing on asthma prevention (n = 355), 2) Efficacy after discontinuation of AIT (n = 293), 3) Fighting severe allergic disease (n = 322), 4) Looking at the present, facing current symptoms (n = 265) and 5) Doctor's own clinical experience (n = 500). Each one of these clusters have specific patients' and doctors' characteristics, representing distinctive AIT prescription drivers. Conclusion: Using data-driven analysis, we identified for the first time some reasons and patterns of AIT prescriptions in real-life clinical settings. There is no uniform indication for prescribing AIT, which varies amongst patients and doctors with multiple but specific drivers, taking into account several relevant parameters.

Lin-Zhe Du, Pei-Yan Liu, Chen-Yan Ge, Yang Li, Yuan-Yuan Li, Mu-Fei Tang, Jin-Jin Chen Department of Clinical Pharmacy, Nanjing First Hospital, Nanjing, People’s Republic of ChinaCorrespondence: Jin-Jin Chen, Department of Clinical Pharmacy, Nanjing First Hospital, No. 68 Changle Road, Qinhuai District, Nanjing, 210006, People’s Republic of China, Tel +86-025-87726312, Email pxchenjin@163.comBackground: Continuous intravenous infusion (IV) or subcutaneous injection (SC) of insulin was widely applied to control hyperglycemia after ischemic stroke. However, the impact of different administration modes on glycemic variability was unknown.Methods: Consecutive stroke patients treated with intravenous thrombolysis were screened. Subjects who received insulin treatment were included and entered into the IV or SC group according to the respective administration mode. Blood glucose was closely monitored within the first 72 hours, and the target range of glucose was from 7.7 to 10.0 mmol/L for all patients. The variabilities of glucose, assessed using standard deviation of the mean, variable coefficient and range from the maximum to the minimum value, were compared between the two groups.Results: A total of 130 patients were enrolled with 66 in the IV groups and 64 in the SC group. Compared with the SC group, the IV group had higher glycemic variability evaluated as either standard deviation (2.7 ± 0.7 mmol/L vs 2.2 ± 0.9 mmol/L, p = 0.002), variable coefficient (0.26 ± 0.06 vs 0.23 ± 0.08, p = 0.011) or range (10.0 ± 3.6 mmol/L vs 8.1 ± 3.1 mmol/L, p = 0.001). Multivariate logistic regression analyses found that continuous intravenous infusion was associated with higher level of the standard deviation (adjusted OR 3.01, 95% CI 1.29– 7.28, p = 0.011), variable coefficient (adjusted OR 5.97, 95% CI 2.55– 13.96, p < 0.001) and range (adjusted OR 6.08, 95% CI 2.63– 14.05, p < 0.001).Conclusion: Continuous intravenous infusion of insulin was associated with higher glycemic variability than subcutaneous injection in acute stroke patients receiving thrombolysis.Keywords: acute ischemic stroke, insulin, continuous intravenous infusion, subcutaneous injection, administration mode

ObjectiveSubcutaneous injection of methylene blue around the anus may help reduce postoperative pain. However, the concentration of methylene blue is still controversial. Therefore, Our study aims to investigate the efficacy and safety of different methylene blue injected concentrations subcutaneously in pain treatment after hemorrhoidectomy.MethodsA total of 180 consecutive patients with grade III or IV hemorrhoids from March 2020 to December 2021 were reviewed. All patients underwent hemorrhoidectomy under spinal anesthesia and were divided into three groups. Group A received subcutaneous injection of 0.1% methylene blue after hemorrhoidectomy, group B received subcutaneous injection of 0.2% methylene blue, and Group C did not received subcutaneous injection of methylene blue. The primary outcome measures were the visual analog scale (VAS) pain score on postoperative days 1, 2, 3, 7, 14, and total analgesic consumption within 14 days. Secondary outcomes were complications after hemorrhoidectomy, including acute urinary retention, secondary bleeding, perianal incision edema, and perianal skin infection, and the Wexner scores used to assess the level of anal incontinence at one and three months after surgery.ResultsThere was no significant difference among three groups in sex, age, course of the disease, hemorrhoid grade and the number of incisions, and there was no significant difference in the volume of methylene blue injected between group A and group B. The VAS pain score and total analgesics consumption within 14 days in group A and group B were significantly lower than those in group C, but the differences between group A and group B were not statistically significant. The Wexner scores of group B were significantly higher than those of group A and group C one month after the operation, but the differences between group A and group C were not statistically significant. In addition, the Wexner score among three groups decreased to zero at three months after operation. There was no significant difference in the incidence of other complications among three groups.ConclusionThe perianal injection of 0.1% methylene blue and 0.2% methylene blue have a similar analgesic effect in pain treatment after hemorrhoidectomy, but 0.1% methylene blue has higher safety.

[Display omitted] • Convective and diffusive transport into the lymphatic system is modeled by a hybrid discrete-continuum vessel network. • Various physiological conditions on the lymphatic vessel wall affects absorption rate. • Evolution of concentration boundary layer is dominated by diffusion across the explicit vessels. • Injection depth shows negligible effect on drug absorption in the multi-layered tissue. • Binding of drug molecules to the extracellular matrix slows down the drug absorption. Subcutaneous administration is a common approach for the delivery of biotherapeutics, which is achieved mainly through the absorption across lymphatic vessels. In this paper, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. We find that the local lymphatic uptake through the explicit vessels significantly affects macroscopic drug absorption. The diffusion of drug solute through the explicit vessel network affects the lymphatic uptake after the injection. This effect, however, cannot be captured using previously developed continuum models. The lymphatic uptake is dominated by the convection due to lymphatic drainage driven by the pressure difference, which is rarely studied in experiments and simulations. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. We find that the injection volume significantly affects the rate of lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence, which is consistent with the experimental results. At last, the binding and metabolism of drug molecules are studied to bridge the simulations to the drug clearance experients. We provide a new approach to study the diffusion and convection of drug molecules into the lymphatic system through the hybrid vessel network. [ABSTRACT FROM AUTHOR]