1st Injection Research Articles

183 Comparison of presynchronization and OvSynch protocols following fixed-time breeding in lactating dairy cattle

Abstract Current study was carried out to compare two presynch-OvSynch protocols with standard OvSynch protocol in postpartum Holstein dairy cattle. Postpartum cows (n = 473) were randomly divided into one of the three protocols: I) G7G-OvSynch (n = 159), cows were subjected to PGF2α followed by GnRH 48 h later. After 7 d post-GnRH injection, standard OvSynch protocol was introduced, II) G7GM-OvSynch (n = 162), cows were subjected to the same protocol as in group I) except one extra PGF2α at 12 h interval in Ovsynch part, and III) standard OvSynch protocol (n = 152). The progesterone (P4) profile was subjected to d 30 and d 60 post FTAI. Ovarian status was monitored at the 1st GnRH, PG, and 2nd GnRH injection of the breeding part. Pregnancy/ AI was diagnosed on d 30,60, and 90 post-FTAI, and pregnancy loss was also on d 60 and 90 post-FTAI. Pregnancy data were analyzed using the Chi-square test and plasma P4 profile by ANOVA using SAS. Ovulatory follicle diameter (mean ± SD) was 15.44 ± 1.24 in G7G-Ovsynch, 15.21 ± 1.36 in G7GM-OvSynch, and 14.90 ± 1.02 in OvSynch, respectively (P > 0.05). Plasma P4 profile (ng/mL; Mean ± SD) on d 30 post TAI was 6.50 ± 1.39,7.01 ± 1.13 and in 6.49 ± 1.32 G7G-OvSynch, G7GM-Ovsynch and OvSynch groups, respectively (P = 0.09). On d 60 post TAI, P4 profile was recorded to be 7.75 ± 1.20, 7.58 ± 1.36 and 6.80 ± 0.96 in G7G-OvSynch, G7GM-OvSynch and OvSynch, respectively (P < 0.05). P/AI on d 30 was 51.57% (83/159), 57.41% (93/162) and 42.76% (65/152) G7G-Ovsynch, G7GM-OvSynch, and OvSynch, respectively (P = 0.033). Similarly, AI on d 60 and d 90 post FTAI was 44.65% (1/159):51.85% (84/162), 38.16% (58/152): 43.40% (69/159) and 51.23% (83/162):36.18% (55/152) in G7G-Ovsynch, G7GM-OvSynch, and OvSynch protocols (P = 0.051: 0.027), respectively. Pregnancy loss on d 60 and d 90 post FTAI was 13.41%: 2.90%, 9.68%: 1.20% and 10.77%: 5.20% in G7G-Ovsynch, G7GM-OvSynch, and OvSynch, respectively (P = 0.73: 0.35). Although statistically non-significant (P = 0.56), overall pregnancy loss on d 90 post-FTAI was also numerically greater in the G7G-OvSynch (15.85%) protocol as compared with G7GM-OvSynch (10.75%) and OvSynch (15.38%). We concluded that the G7GM-OvSynch protocol has resulted in an increased P/AI, P4 profile in comparison with G7G-OvSynch and OvSynch. Similarly, pregnancy loss was also less in the G7GM-Ovsynch protocol, which makes it a protocol of choice for postpartum dairy cows.

Intravitreal Injections of Bevacizumab (Avastin); which Dose is Recommended?

This study was conducted to evaluate the fast improvement, effectiveness & safety of intravitreal injections bevacizumab (Avastin), in different doses, for treating diabetic macular edema (DME). Eyes of 80 patients with diabetic macular edema were randomized and planned to receive three consecutive monthly intravitreal injections of 1.25 mg or 2.5 mg bevacizumab (forty patients for each group). Patients were observed for 4 weeks after 1st injection and the changes in the best-corrected visual acuity (BCVA), central macular thickness (CMT) and adverse events were compared between both groups. CMT was significantly reduced in both groups (P < 0.013). Significant improvements between baseline and 2weeks to 4weeks in the 2.5 mg group, were mean decrease in CMT was 318 t0 182(P<.001), mean BCVA is 0.16 improve to 0.7 and P value 0.001. Intraocular pressure (IOP)measurements post intravitreal (IV) bevacizumab injection was not raised its statistically significant (P < 0.001). CMT improvement with a dose of intravitreal IV injection 2.5 mg is promising a rapid safe effective response for treating DME without any ocular or systemic side effects but Follow-up is still short to make any specific treatment recommendations.

A phase 1/2 study of vusolimogene oderparepvec (RP1) in primary melanoma (mel) to reduce the risk of sentinel lymph node (SLN) metastasis.

TPS9614 Background: The majority of the 80,000 newly diagnosed mel patients in the US have localized early-stage disease and undergo wide local excision (WLE) with or without SLN biopsy. The SLN is a critical prognostic marker and pivotal to immune response initiation, and fosters tumor-mediated immune suppression and pre-metastatic niches. Thus, SLN is a key target for local immune intervention. Vusolimogene oderparepvec (RP1), a locally administered oncolytic immunotherapy, provides a unique opportunity for intervention following mel diagnosis, prior to definitive surgical management. Derived from the HSV1 strain RH018A, RP1 exhibits superior killing on human tumor cell lines, designed with deletions in neurovirulence factors (ICP34.5 and ICP47) and immune-stimulating elements (increased US11 expression, GM-CSF and GALV-GP R-) to maximize oncolytic potency and induce cell death. Preclinical and clinical data demonstrate RP1's robust antitumor efficacy in advanced mel. This trial addresses a crucial gap in understanding RP1's impact on SLN dynamics, holding promise for preventing disease recurrence in this high-risk population. We hypothesize that in mel patients with high risk, clinically node negative disease (pT3b-T4b), administration of RP1 will reduce rates of SLN positivity compared to a historic control by favorably reshaping the immune landscape of the primary tumor, SLN and peripheral blood. Methods: This investigator-initiated, single site, open label, non-randomized phase 1/2 pilot study (NCT06216938) will enroll 25 patients with high-risk, clinically node-negative mel (pT3b-T4b). Major eligibility criteria include diagnosis of pT3b, T4a, or T4b non-uveal mel with visible residual tumor or positive initial biopsy margins, ECOG 0 or 1 and adequate organ function on screening labs. Patients will receive 3 doses (1ml/dose) of RP1, locally injected at the primary tumor site before standard WLE and SLN biopsy (SLNB). The first dose on day 1 will be 10e6 pfu/ml, followed by 10e7 pfu/ml for the next two doses on days 15 and 21, administered over 4-5 weeks before WLE and SLNB. Surgery occurs within 35 days of the 1st RP1 injection to avoid delays in definitive treatment. Biopsies and blood samples are obtained pre- and post-treatment. Patients will be followed for up to 3 years. Safety assessments include physical exams, labs, and adverse events (AE) monitoring. The primary endpoint is the rate of SLN positivity in the overall cohort, calculated by comparing the observed rates to the expected number of positive SLNs for that cohort using the Melanoma Institute of Australia's Prediction Tool. Secondary endpoints include safety and tolerability of RP1, RFS and OS. Exploratory correlative assays will compare the immunophenotype in primary tumor and the SLN (IHC) and in peripheral blood (flow cytometry) between baseline and on treatment. Clinical trial information: NCT06216938 .

Near vision in patients with DME and RVO treated with aflibercept and correlation with NEI VFQ-25 questionnaire

BackgroundThe aim of this study is to evaluate near and distance visual acuity (VA) and their correlation with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) outcomes in patients with diabetic macular edema (DME) and macular edema due to retinal vein occlusion (RVO) treated with aflibercept.MethodsIn this prospective study, we included 87 eyes of patients diagnosed with DME (n = 61) and RVO (n = 26), who received aflibercept treatment and were followed until the 8th injection. Near VA was examined on the 1st, 2nd, 3rd, 4th, 6th, and 8th injection, and patients completed the NEI VFQ-25 on the 1st, 4th, and 8th aflibercept injection.ResultsThe mean near VA at baseline in all eyes was 0.89 ± 0.12 logMAR. With every administration, there was a statistically significant improvement; on the 4th (0.70 ± 0.19; p = 0.000) and the 8th application (0.60 ± 0.19; p = 0.000). At baseline, the mean NEI VFQ-25 total score was 71 ± 14%, and improved to 81 ± 13% (p = 0.000) on the 8th injection. The most significant score gain was recorded in the near VA subscale (+ 20 ± 14%, p = 0.000). There was no statistically significant difference between DME and RVO group in the questionnaire or near VA outcomes.ConclusionAflibercept treatment resulted in a remarkable improvement of near vision by 4 lines of logMAR optotype after the 8th application. The near vision questionnaire subscale, initially scoring the lowest, exhibited the greatest gain during the treatment period. This underscores the importance of near vision and reading ability for patients with DME and RVO.

The factors associated with retinal pigment epithelium tear development in the early phase after treatment initiation for age-related macular degeneration.

This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3months of starting anti-VEGF therapy was examined. This study included 244 eyes (230 patients; mean age 75.0years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07-2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22-7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12-850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs.

Abstract CT004: A single arm phase 2 study of TVEC in patients with invasive cutaneous SCC: A novel therapeutic approach for low risk tumors

Abstract Background: Immune recognition and cytotoxic responses play an important role in the pathogenesis and progression of cutaneous squamous cell carcinoma (cSCC). Talimogene laherparepvec (TVEC) is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells, and induces production of GM-CSF to enhance systemic antitumor immune priming. This proposed mechanism of action supports the novel approach to implement TVEC in the management of cSCC, particularly, in patients with increased burden of primary tumors. Methods: Study subjects were Immunocompetent, ≥ 18 years of age, and diagnosed with at least one histologically confirmed primary low-risk cSCC according to the Brigham and Women staging system. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions included target lesions injected (TLIs) and target non-injected lesions (TNILs). TNILs were selected to evaluate for abscopal effect when feasible. The TLIs were treated according to TVEC FDA approved protocol and followed for 1yr after the 1st injection. The primary study endpoint was to evaluate the overall response rate, defined as the proportion of subjects who achieved complete response and partial response in the TLIs. Safety and adverse effect profile (AEs), duration of response, time to response, durable response rate, and time to progression, were the secondary endpoints. A Simon 2 stage design was used. Total sample size was calculated to be 20 subjects. A total of 11 subjects were recruited, due to the COVID-19 pandemic and 100% CR observed in the interim analysis. NCT 03714828. Results: The analysis was conducted after all 11 participants completed Visit 8 (230-271 days from study initiation). Conclusions: TVEC showed extremely impressive ORR for patients with cSCC with a 95.8% CR for TLIs. AE profile of TVEC was mild and was well tolerated. Further studies evaluating the role of intralesional immunotherapy should be considered in patients with increased burden of cSCC. Table 1. summarizes the study results. For the primary endpoint 100% of participants achieved an overall response. Primary outcomes for patients (n = 11) Secondary outcomes for TLIs (n = 24) Time to response - days Mean ± standard deviation Median/Range (min, max) 41.6 ± 24.9 Time to response - days Mean ± standard deviation Median/Range (min, max) 48.7 ± 29.2 35/(18 - 112) 35/(18 - 112) Final response to TVEC - % Overall response rate (ORR) Partial response (PR) Complete response (CR) 100% (11/11) 9.1% (1/11) Response to TVEC - Overall response rate (ORR) Partial response (PR) Complete response (CR) 100% (24/24) 90.9% (10/11) 4.2% (1/24) 95.8% (23/24) Duration of response - days Mean ± standard deviation Median - Range (min, max) 206.0 ± 26.0 Duration of response - days Mean ± standard deviation Median - Range (min, max) 201.4 ± 29.6 212 (140 - 236) 209 (136 - 250) Durable response rate - % 90.9% (10/11) Durable response rate - % 83.3% (20/24) Secondary outcomes for TNILs (n = 2) Final response to TVEC - % 100% (2/2) Adverse Events NCI CTCAE (v. 4.0) Event n (%) 95% CI Severity Mild (Grade 1) Moderate (Grade 2) Fatigue 5 (45.5%) (16.7%, 76.6%) 4 (80%) 1 (20%) Flu-like symptoms 4 (36.4%) (10.9%, 69.2%) 3 (75%) 1 (25%) Headache 2 (18.2%) (2.3%, 51.7% 2 (100%) Citation Format: Clara Curiel-Lewandrowski, Delaney B. Stratton, Anngela C. Adams, Haiyan Cui, Denise Roe, Srinath Sundararajan. A single arm phase 2 study of TVEC in patients with invasive cutaneous SCC: A novel therapeutic approach for low risk tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT004.

Частота рецидивов ретинопатии недоношенных после введения ингибиторов ангиогенеза (афлиберцепта) в зависимости от массы тела ребенка

Purpose. To study the effectiveness of treatment and the causes of reactivation of retinopathy (ROP) in premature children after aflibercept injection. Material and methods. This study was conducted at the V.F. Voino-Yasenetsky Scientific and Practical Center for Specialized Medical Care in Children from September 2021 to February 2023. The study included 122 premature infants (244 eyes) with ROP who received intravitreal administration of aflibercept. Patients were divided into two groups: the main group (reactivation group) consisted of children who received two or more intravitreal injections of VEGF inhibitors (aflibercept) and the control group consisted of children who received a single intravitreal injection of VEGF inhibitor (aflibercept) with a positive effect. In addition, 3 subgroups were identified depending on birth weight: 37 children had a birth weight of less than 900 g (1st subgroup), 41 children weighed from 900 to 1200 g (2nd subgroup), and 44 children weighed more than 1200 g (3rd subgroup). All patients were monitored for reactivation of ROP after intravitreal injection of aflibercept. Results. Since 2010, we have been using angiogenesis inhibitors in the treatment of ROP. The effectiveness of one dose of aflibercept (0,5 mg/0,0125 ml) is 84,84%. Repeated injections are easily tolerated by patients and increase the effectiveness of treatment to 99,76%. The work is devoted to the analysis of reactivation of ROP after one injection of aflibercept and the study of the reasons for repeated injections. 37/244 eyes (15,16%) showed reactivation of ROP after one injection. Factors influencing the reactivation of retinopathy of prematurity after intravitreal injection of aflibercept include: gestational age, postconceptual age at the 1st injection, birth weight, weight at the 1st injection, birth height, newborn head circumference, head circumference at the 1st injection, newborn chest circumference, history of blood transfusions, body mass index (BMI) at the 1st injection, nuchal cord complications. A large dependence of the reactivation rate on the child’s weight was noted. The birth weight subgroup of less than 900 g had a recurrence rate of 28,38%, followed by the average birth weight subgroup (12,20%) and the subgroup weighing more than 1200 g (6,82%). The reactivation time in the three subgroups of patients was 9,82±5,76, 10,20±3,27 and 12,33±9,24 weeks, respectively. The time of reactivation was also determined by the child’s weight. Reactivation occurred earlier in children with lower weight: in three subgroups of patients, 9.82±5.76, 10.20±3.27 and 12.33±9.24 weeks, respectively. Conclusion. Based on our research, the frequency of reactivation of ROP depends on the weight of the premature baby. A change in weight, even by 100 grams, changes the course of ROP. The lower the birth weight is, the higher the reactivation rate of ROP becomes. Reactivation of ROP occurs 4 times more often (in every 3–4 children) in children with very low birth weight (less than 900 g). The frequency of reactivation is also determined by the weight of the child during the first injection of an angiogenesis inhibitor. Weight also determines the time of reactivation, occurring in children weighing less than 900 or 9–10 weeks after the first injection. If there are risk factors, it is advisable to: carry out simultaneous injections in both eyes, which will increase the dose of aflibercept in total, carefully monitor them in the first 2 months with examination of the fundus, or increase the dose of the drug. Effectiveness can be enhanced by ingesting synergists or impact of physiotherapy. Key words: recurrence, reactivation, retinopathy of prematurity, risk factor, birth weight, intravitreal injection, aflibercept, vascular endothelial growth factor

Prediction of neovascular age-related macular degeneration recurrence using optical coherence tomography images with a deep neural network

Neovascular age-related macular degeneration (nAMD) can result in blindness if left untreated, and patients often require repeated anti-vascular endothelial growth factor injections. Although, the treat-and-extend method is becoming popular to reduce vision loss attributed to recurrence, it may pose a risk of overtreatment. This study aimed to develop a deep learning model based on DenseNet201 to predict nAMD recurrence within 3 months after confirming dry-up 1 month following three loading injections in treatment-naïve patients. A dataset of 1076 spectral domain optical coherence tomography (OCT) images from 269 patients diagnosed with nAMD was used. The performance of the model was compared with that of 6 ophthalmologists, using 100 randomly selected samples. The DenseNet201-based model achieved 53.0% accuracy in predicting nAMD recurrence using a single pre-injection image and 60.2% accuracy after viewing all the images immediately after the 1st, 2nd, and 3rd injections. The model outperformed experienced ophthalmologists, with an average accuracy of 52.17% using a single pre-injection image and 53.3% after examining four images before and after three loading injections. In conclusion, the artificial intelligence model demonstrated a promising ability to predict nAMD recurrence using OCT images and outperformed experienced ophthalmologists. These findings suggest that deep learning models can assist in nAMD recurrence prediction, thus improving patient outcomes and optimizing treatment strategies.

Long-acting prescriptions and therapy for HIV-1 from market launch to the present in Germany (May 2021 to December 2023).

In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany. Based on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation. The bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was €11,940 (maintenance therapy with initiation) and €10,950 (maintenance therapy without initiation). To our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.

Use of botox for sialorrhea and dysphagia in the neonatal population

IntroductionBotox is frequently used for sialorrhea in patients with compromised airways and those with etiologies causing difficulty with secretion management (i.e. strokes, neurologic disorders, etc.). There are no published studies regarding the use of botulinum toxin (BoNT) in the neonate population. We aim to discuss our experience and safety of BoNT use in the neonate population in regards to alleviating secretion management and airway protection. MethodsRetrospective review of neonates admitted to the neonatal intensive care unit (NICU) ≤12 months of age who received BoNT injection to submandibular (SMG) and parotid (PG) glands for sialorrhea/dysphagia. BoNT was administered under ultrasound (u/s) guidance by interventional radiology. Results6 children were examined. 2 (33 %) were male. Avg NICU stay was 87.5 ± 33.1 days. 2 underwent surgical airway intervention prior to injection. Mean age at initial BoNT was 1.5 ± 0.7 months. Avg weight at injection was 4 ± 1.1 kg. Each PG and SMG were injected in 5/6 cases. Bilateral SMG were unidentified on u/s in 1 case and thus not injected. Dose range injected per gland was 5-15u. 100 % required tube feeds, 50 % with tubes distal to stomach (NJT/NDT). 83 % were completely NPO prior to injection and there was no noted clinical improvement in oral skills post injection. All had noted desats/apneas prior to injection and 83 % had reported decreased events post injection. 50 % had reported decrease O2 requirements and frequent suctioning 2wks after injection, however 2 (33 %) required surgical airway intervention after injection (trach, SGP/MDO). 4/6 (67 %) trialed medical therapy, anticholinergics being the most common. 50 % underwent 2nd injection (age = 6.5 ± 0.3 months) avg. 4.7 ± 0.7mo after 1st injection, and the same 3pts underwent 3rd injection (age = 12.5 ± 2.4 months) avg. 6.1 ± 2.5mo after 2nd injection. 1 pt. had a total 6 injections. There were no injection related complications. ConclusionBoNT injection is a safe, non-invasive alterative for management of sialorrhea in neonates. Further extensive study needs to be performed to identify the optimal dose per gland in this population.

Outcomes following Intra-Articular Hyaluronic Acid Injection for the Management of Hallux Rigidus: A Systematic Review

Category: Midfoot/Forefoot; Other Introduction/Purpose: The purpose of this systematic review was to evaluate outcomes following intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus. Methods: During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies evaluating outcomes in patients who underwent intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus. Data regarding injection characteristics, subjective clinical outcomes, failure rates and complications were extracted and analysed. Results: In total, 5 studies were included in this review. In total, 209 patients underwent intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus at a weighted mean follow-up of 4.4 ± 1.4 months. The weighted mean VAS improved from a pre-injection score of 6.4 ± 0.3 to a post-injection score of 2.8 ± 0.4. A 10.1% complication rate was noted, the most common of which was transient 1st MTPJ swelling. One infection (0.5%) was reported. A symptomatic recurrence rate of 18.6% was observed at a weighted mean time of 7.3 ± 4.2 months Conclusion: This systematic review demonstrated that intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus led to a reduction in pain and a moderate complication rate at short-term follow-up. In addition, intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus produced a symptomatic recurrence rate of 18.6% at approximately 7.3 months, suggesting that HA provides short-term relief. The lack of quality comparative studies limits the generation of robust conclusions, reinforcing the need for further research to identify the optimal role of HA in the management of hallux rigidus.

Catalyst-heating operation in compression-ignition engines: A comprehensive understanding using large eddy simulations

Catalyst-heating operation in compression-ignition engines is critical to ensure rapid light-off of exhaust catalysts during cold-start. This is typically achieved by using late post injections for increased exhaust enthalpy, where retardability is constrained mainly by emissions due to inactivity of the oxidation catalyst at these conditions. Comprehensive understanding of formation mechanism of pollutant emissions is needed to optimize engine performance and minimize tailpipe harmful emissions. In this study, a computational fluid dynamics model of a medium-duty compression-ignition engine is developed and validated against with catalyst-heating operation experimental data using large eddy simulations. The engine is fueled with a full boiling-range diesel fuel and uses an optimized five-injections strategy that consists of two pilots, one main, and two post injections. Results show that, significant amounts of unburned hydrocarbons (UHCs) and oxygenated UHCs (OUHC) are formed by the pilot injections, which may persist until exhaust valve opening. UHCs accumulate mainly in the outer-upper part of the cylinder guided by the piston lip, in the inner-bowl due to the bowl geometry, near the injector nozzle by the fuel from the end-phase of injection, and in the space between spray plumes transported by the swirl motion. The main injection exhibits a short ignition delay and rapidly consumes most of UHC and OUHC, except for the central part of the chamber near the injector nozzle. The 1st post injection counteracts the expansion effect on temperature, plays a key role in increasing the exhaust enthalpy and reducing the harmful emissions by promoting combustion associated with the 2nd post injection. The fuel delivered by the 2nd post injection penetrates through the flame of the 1st post injection, creating cool flame clouds beyond the flame that eventually transition to a diffusion flame. Finally, a unique phenomenological model is proposed to better visualize the interactions of post injections.

Effect of Platelet Rich Plasma Therapy for Shoulder Osteoarthritis: Double Blinded Randomized Controlled Study

Abstract Background Platelet-rich plasma (PRP) is widely used in musculoskeletal conditions and orthopaedic surgery ranging from clinic-based injections for tendinopathies to intra-operative application to augment soft-tissue healing. It has been used in knee osteoarthritis, rotator cuff tears, elbow epicondylitis, anterior cruciate ligament reconstruction, shoulder impingement syndrome and various tendinopathies to date, with an expanding list of indications. While available evidence supports the use of PRP in the management of lateral epicondylitis and knee osteoarthritis, there is limited clinically significant evidence for other indications Aim of the Work This study aims to evaluate the efficacy of platelet-rich plasma as a treatment for primary and secondary shoulder osteoarthritis pain. Patients and Methods A prospective, double-blinded randomized control study in Ain Shams University Hospitals from 3 to 6 months. The patients were divided into 2 groups using computerized generated randomization. The control group received 5 ml 0.9% saline injection in the intra-articular shoulder (between glenohumeral joint). The study group received 5 ml of PRP treatment. Results The study results showed: All demographic data (age, sex, weight and BMI) and chronic diseases were insignificantly different between both groups, all medical data (chronic diseases, type of osteoarthritis, severity of symptoms, time of symptoms, radiological finding and type of treatment) were insignificantly different between both groups, NRS was significantly lower in study group compared to control group at ―2nd evaluation post injection|| and was insignificantly different between both groups at ―1st evaluation post injection||. (P < 0.05), range of movement was insignificantly different between both groups at 2nd evaluation post injection and injection related complications (inflammation and infection) were insignificantly different between both groups. Conclusion In general, efficacy was observed in treatment with PRP alone in shoulder osteoarthritis. However, patients receiving PRP treatment are less likely to experience post-injection pain and are more likely to recover faster when compared to patients receiving saline alone.

1674-P: Increased Glucose Uptake in Brown Fat Promotes Energy Expenditure

Brown and beige fat dissipate energy as heat in response to β3-adrenergic receptor (β3AR) stimulation. Strategies to facilitate this response may be employed to promote weight loss and improve health in patients with metabolic disease. Previously, we discovered that GTPase RalA and its GAP complex RalGAP regulate exocytosis of glucose transporter GLUT4. We demonstrated in vivo, that adipose-tissue specific knockout of RalGAP subunit RalGAPB activates RalA and increases glucose uptake 7 times in brown fat (BAT), leading to improved glucose handling on high fat diet (HFD). Here we seek to test the effect of increased glucose uptake in BAT on energy expenditure (EE), using mice with BAT-specific knockout of RalGAPB (the KO mice). After 8 weeks on 45% HFD, the KO mice and control littermates (Ctr) were injected with β3AR agonist CL-316,243 (CL) or PBS for 8 days. Mice assigned to CL were placed in metabolic cages. Respiratory quotient was increased in the KO mice, indicating increased glucose oxidation (likely by BAT, due to increased glucose uptake). EE at room temperature was elevated in the KO mice. This was compensated by increased food uptake, explaining similar body weights between the KO and Ctr mice. CL injections, as expected, induced spikes in EE. Acute response to CL (arbitrarily defined as EE during 2 hours after CL injection) was consistent between daily CL injections in Ctr mice, and was increased twice in the KO mice compared to Ctr. In Ctr mice, 1st CL injection increased average day and night EE; this response gradually declined with consecutive CL injections. In the KO mice, 1st CL injection elicited similar to Ctr mice increase in average day and night EE; and the response to consecutive CL injections was preserved. As anticipated, CL reduced adiposity in Ctr mice, which was further augmented in the KO mice, consistent with finding on EE. We will further test the role of increased glucose uptake by BAT in EE of the KO mice, and will determine the mechanism of sustained CL responsiveness in the KO mice. Disclosure F.Rezayat: None. J.A.Resnick: None. I.M.Farah: None. Y.Skorobogatko: None. A.Saltiel: Board Member; Elgia Therapeutics. Funding National Institutes of Health (P30DK063491)

Expression of genes for transport of water and angiogenesis, as well as biochemical biomarkers in Holstein dairy cows during the ovsynch program

Changes in expression of genes associated with angiogenesis and transport of water by cells, as well as biomarkers of oxidative stress were determined at specific times during the ovsynch protocol to synchronize estrus and breed Holstein dairy cows. Blood samples were taken from 82 lactating Holstein cows at the time of the 1st GnRH injection (G1), 7 days later at the time of the PGF2a (PG) injection, and 48 h after the PGF2a treatment when the second injection of GnRH was administered (G2). The serum was analyzed for malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase (GPX), nitric oxide (NO), catalase (CAT), and total antioxidant capacity (TAC). The expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS3), aquaporin 3 (AQP3), and AQP4 mRNAs in peripheral blood mononuclear cells (PBMCs) was analyzed. The number of copies of each of the mRNAs was quantified using qPCR. Pregnancy status was determining at 32 ± 3 days after insemination using an ultrasound “Sonoscape-5V″ model. Receiver operating curves (ROC) were used to assess the sensitivity and specificity of the biochemical parameters in serum to predict establishment of p The expression of MDA, GPX, and Catalase changed (P < 0·05) between G1, PG and G2 phases of the ovsynch protocol with higher levels at PG than at G1 and G2. The highest levels of NO were detected at G2. The ROC analyses identified NO, TAC and CAT as the most sensitive and specific biomarker for pregnancy with areas under the curve being 0.875 (P < 0.0001), 0.843 (P < 0.03), 0.833 (P < 0.017), sensitivity being 75.3, 42.86, and 26.27%, and specificity being 90, 90 and 85% respectively. The expression for VEGF, VEGFR2, eNOS3, AQP3, and AQP4 mRNAs was upregulated at PG compared to G1 and G2 phases of the ovsynch protocol. The results suggest that following the first injection of GnRH, there is an increase in expression of VEGF, VEGFR2, eNOS3, AQP3, and AQP4 mRNAs by the time of the PGF2a injection and then expression decreased. Further, ROC analyses identified increases in NO, TAC and CAT as the most sensitive and specific biomarkers with the greatest potential to predict establishment of pregnancy in Holstein cows.

A phase 1 first-in-human study of interferon beta (IFNβ) and membrane-stable CD40L expressing oncolytic virus (MEM-288) in solid tumors including non–small-cell lung cancer (NSCLC).

2569 Background: MEM-288 is a conditionally-replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell-mediated systemic T cell responses capable of inhibiting abscopal tumor growth as monotherapy and synergizes with immune checkpoint inhibitors (ICI). Methods: MEM-288 is being evaluated in this Phase 1 open-label trial (NCT05076760) in pts with select solid tumors including NSCLC (a) refractory to standard therapy and (b) with a tumor lesion deemed feasible for biopsy and MEM-288 intratumoral (i.t.) injection. The primary objective is to determine using a BOIN design a recommended phase II dose of MEM-288 across 3 dose levels (DL1-3) spanning 1e10 to 1e11 viral particles by i.t. injection once every 3 weeks. Secondary objectives include efficacy assessment, including response rate of injected and non-injected tumors assessed separately. Tumor biopsies obtained immediately prior to the 1st and 2nd injections are used to explore biomarkers and anti-tumor immune responses. Results: As of February 2023, 12 pts (11 NSCLC and 1 pancreatic cancer; n = 3 DL1, n = 5 DL2, n = 4 DL3) have enrolled. The median number of MEM-288 i.t. injections was 2 (1-3), median age was 63 (39-76), and median prior lines of therapy was 3 (1-5). Radiology-guided injections were administered in superficial/palpable tumors and visceral lesions. No dose limiting toxicities occurred. Treatment-related adverse events observed in &gt; 1 pt include grade 1 injection site reaction (42%) and chills (17%). Of 10 response-evaluable pts, 4 (40%) pts had shrinkage of injected tumor (range -26 to -54%): 3 (30%) PR and 1 (10%) SD. Multiple pts also had stabilization or shrinkage of distal non-injected lesions. Best overall response was 3 (30%) stable disease and 7 (70%) progressive disease. After a single MEM-288 injection, biopsies show decreased tumor cell percentage concomitant with substantial increases in overall CD8+ T cells, increased T clonotype diversity in both tumor and peripheral blood, and increased TCF1+ stem-like CD8+ T cells that are strongly associated with response to ICIs. Plasma cytokine analysis showed increases in IFNg and of IFN-inducible cytokines and chemokines, supportive of stimulation of systemic response after MEM-288. Of note, a pt with strong stimulation of tumor and systemic T cell immunity after MEM-288 had subsequent CR (ongoing &gt; 7 months) to docetaxel + ramucirumab following prior treatment failure with platinum doublet + ICI received before MEM-288. Conclusions: Preliminary safety, antitumor and immune response data are encouraging. Updated results and immune data from this study will be presented. An expansion arm is planned with combination MEM-288 and anti-PD1 antibody in pts with advanced NSCLC refractory to ICI. Clinical trial information: NCT05076760 .

Исследование непосредственной клинической эффективности бролуцизумаба при лечении ВМД

Purpose. Analysis of direct clinical efficacy of brolucizumab in choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). Material and methods. A clinical evaluation of effectiveness of using Beovu® (Novartis Pharma AG, Switzerland) was carried out in 25 patients (25 eyes) with neovascular AMD, mean age old patients was 68 ± 5 years. Dynamic monitoring was carried out using optical coherence tomography: localization and area of neovascular complex, density and thickness of newly formed vessels (angiography mode). 3 monthly injections of Beovu® were performed (at a dose of 6.0 mg/0.05 ml). The observation period was 4 months. Results. After the 1st injection of Beovu®, there was statistically significant decrease in the average indexes of central retinal thickness (CRT) and macular volume (MV) relative to initial. At the same time, an increase in best corrected visual acuity (BCVA) was observed (p = 0.044). A similar trend persists for average values of CRT and MV after each of the 3 injections. It is noteworthy that in all patients, after 3 injections, the minimum values of CRT were achieved – 268 (263; 270) versus 298 (284; 302) µm (p &lt; 0.001). There was also a clear trend towards an increase in BCVA from 0.3 (0.2; 0.45) to 0.6 (0.4; 0.6) in all studied cases (p &lt; 0.001). In 22 of 25 patients, after 1 month, adhesion of the neuro- and pigment epithelium was recorded with complete resorption of subretinal fluid, in 3 patients – after three monthly intravitreal injections of Beovu®, while the subretinal fluid was not recorded in them. Subjectively, all patients noted improvement in quality and contrast of central vision in the operated eyes. Conclusion. After each injection of Beovu®, there was progressive statistically significant reduction in macular area parameters – CRT and MV in combination with an increase in mean BCVA values from 0.3 (0.2; 0.45) initially to 0.6 (0.4; 0.6) by the 4th month of observation. Keywords: vascular endothelial growth factor, anti-VEGF, brolucizumab, Beovu®, age-related macular degeneration, neovascular age-related macular degeneration, wet age-related macular degeneration

Adapted "Break the Cycle for Avant Garde" intervention to reduce injection assisting and promoting behaviours in people who inject drugs in Tallinn, Estonia: A pre- post trial.

In the context of established and emerging injection drug use epidemics, there is a need to prevent and avert injection drug use. We tested the hypothesis that an individual motivation and skills building counselling, adapted and enhanced from Hunt's Break the Cycle intervention targeting persons currently injecting drugs would lead to reduction in injection initiation-related behaviours among PWID in Tallinn, Estonia. For this quasi-experimental study, pre-post outcome measures included self-reported promoting behaviours (speaking positively about injecting to non-injectors, injecting in front of non-injectors, offering to give a first injection) and injection initiation behaviours (assisting with or giving a first injection) during the previous 6 months. Of 214 PWID recruited, 189 were retained (88.3%) for the follow-up at 6 months. The proportion of those who had injected in front of non-PWID significantly declined from 15.9% to 8.5%, and reporting assisting with 1st injection from 6.4% to 1.06%. Of the current injectors retained in the study, 17.5% reported not injecting drugs at the follow up. The intervention adapted for the use in the setting of high prevalence of HIV and relatively low prevalence of injection assisting, tested proved to be effective and safe.

EFFECT OF PRE- AND POST-MATING VITAMINS AD3E TREATMENT ON REPRODUCTIVE PERFORMANCE OF AWASSI EWES

This study was designed to investigate the influence of pre-estrus (PE) synchronization and post-mating (PM) vitamins AD3E treatment on the reproductive performance of Awassi ewes raised at four Iraqi provinces. Seventy six Awassi ewes were randomly divided within each province into two groups. The first group (n=15, except for Karbala, n= 11) were im injected with five AD3E injections (150 IU / dose), biweekly interval. The 1st injection was 1.5 months PM, while the 2nd and 3rd injections were at the time of progestagen-impregnated vaginal sponges insertion. The 4th injection was at the time of the vaginal sponge’s removal, whereas the 5th injection was 14 days PM. The control group (n=5) was intramuscularly injected with 5 ml normal saline at similar periods. The AD3E groups exhibited higher (P≤0.01) fertility and conception rates as compared to the control groups in Al-Najaf and Karbala provinces. Higher (P≤0.01) lambing rate and liter size were noticed in AD3E groups than those of the control group for all provinces. In conclusion, pre-estrus synchronization and post-mating vitamin AD3E treatment improved the reproductive performance of Awassi ewes.

Abstract CT103: A phase 1 first-in-human study of MEM-288 oncolytic virus in solid tumors including non-small cell lung cancer (NSCLC): impact on tumor and systemic T cell immunity

Abstract Background: MEM-288 is a conditionally-replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell-mediated systemic T cell responses capable of inhibiting abscopal tumor growth as monotherapy and synergizes with immune checkpoint inhibitors (ICI). Methods: Safety, antitumor and immunologic activity of MEM-288 are being evaluated in this Phase 1, multicenter, open-label trial (NCT05076760). Pts with select solid tumors including NSCLC (a) refractory to standard therapy and (b) with a tumor lesion deemed feasible for biopsy and MEM-288 intratumoral injection are eligible. The primary objective is to determine a recommended phase 2 dose of MEM-288 monotherapy across 3 dose levels (DL1-3) spanning 1e10 to 1e11 viral particles by intratumoral injection once every 3 weeks, for up to 6 injections, using a BOIN design. Secondary objectives include efficacy assessment (including response rate of injected and non-injected tumors assessed separately). Tumor biopsies immediately prior to the 1st and 2nd injections, and peripheral blood at serial timepoints, are used to explore biomarkers and anti-tumor immune responses. Results: As of Jan 2023, the study is ongoing with the DL3 high-dose cohort completing accrual. 11 pts (10 NSCLC and 1 pancreatic) enrolled and received ≥1 dose of MEM-288 (n=3 DL1, n=5 DL2, n=3 DL3). No dose limiting toxicities have been reported to date and no pts have discontinued treatment due to toxicity. Treatment-related adverse events observed in &amp;gt;1 pt include grade 1 injection site reaction (45%) and chills (18%). Of 7 pts evaluable for response, 3 had shrinkage of injected tumor (range -40 to -54%), and multiple pts also had stabilization or shrinkage of distal non-injected lesions with best RECIST response in uninjected tumors as 2 SD and 5 PD. After a single MEM-288 injection, biopsies show decreased tumor cell percentage concomitant with substantial increases in overall CD8+ T cells, increased T clonotype diversity in both tumor and peripheral blood, and increased TCF1+ stem-like CD8+ T cells that are strongly associated with response to ICIs. Plasma cytokine analysis showed increases in IFNγ and of IFN-inducible cytokines and chemokines, supportive of stimulation of systemic response after MEM-288. Of note, a pt with strong stimulation of tumor and systemic T cell immunity after MEM-288 had a subsequent CR (ongoing &amp;gt;6 months) to docetaxel + ramucirumab following prior treatment failure with platinum doublet + ICI received before MEM-288. Conclusions: Preliminary safety, antitumor and immune response data are encouraging. Updated results and immune data will be presented. An expansion arm is planned with combination MEM-288 and anti-PD1 antibody in pts with advanced NSCLC refractory to ICI. Citation Format: Andreas N. Saltos, Christy Arrowood, Georgia Beasley, James Ronald, Ghassan El-Haddad, Uzma Khan, Luiziane Guerra-Guevara, Steven Wolf, Lin Gu, Xiaofei F. Wang, Dana Foresman, Xiaoqing Yu, Mark J. Cantwell, Scott J. Antonia, Amer A. Beg, Neal E. Ready. A phase 1 first-in-human study of MEM-288 oncolytic virus in solid tumors including non-small cell lung cancer (NSCLC): impact on tumor and systemic T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT103.